(Title of the Thesis)*

INVESTIGATIONS INTO ENANTIOSELECTIVE BORO–ION CATALYSIS

Brian P. Bestvater

A thesis submitted to the Department of Chemistry

In conformity with the requirements for

the degree of Master of Science

Queen’s University

Kingston, Ontario, Canada

(March, 2017)

1,2,3-Triazolylidene carbene stabilized borenium ions were investigated as frustrated

Lewis pair (FLP) type hydrogenation catalysts and were found to be able to effect the hydrogenation of imines and N-heterocycles at ambient and near ambient pressures and temperatures. The unprecedented activity of our MIC-borenium ion catalysts was attributed to the high σ-donating ability of 1,2,3-Triazolylidene-based carbenes producing an exceptionally stable and active borenium ion catalyst.

Several modifications to the original catalyst structure were employed in an attempt to develop an enantioselective variant of our MIC-borenium ion catalyst. One of the modification to impart asymmetry into the reaction manifold that was investigated in this thesis was the use of a chiral borane, specifically the 9-borobicyclo[3.3.2]decanes (BBDs), in place of the achiral 9-BBN present in the original catalyst design. Disappointingly catalyst stability proved to be highly problematic leading to a difficulty in synthesizing the necessary carbene-borane and resulting in a highly unstable and ineffective catalyst.

During the course of our studies into enantioselective borenium ion catalyzed hydrogenations we became concerned with the facility of hydride abstraction by MIC-borenium ions and whether or not this would result in the racemization of enantioenriched α-N sp3 C–H centres. NMR studies revealed that our MIC-borenium ion catalyst was not able to abstract hydrides from α-N sp3 C–H’s at ambient temperatures and only appreciable rates of hydride abstraction were observed at elevated temperatures of 60 °C. This led us to conclude that the reversibility of the hydride addition could not account for poor enantioselectivity observed for chiral borenium ion catalyzed hydrogenations and showed that an enantioselective MIC-borenium ion catalysts should be possible.

The MIC-borenium ions were also investigated for their ability to activate Si–H bonds, and if they could be used to catalyze the hydrosilylation of C=N functionalities. The MIC-borenium ii ions were found to be highly active hydrosilylation catalysts, able to tolerate a variety of functional groups and able to effect the rapid reduction of imines under ambient conditions.

Finally BBD based borohydrides were also investigated as enantioselective nucleophilic hydrosilylation catalysts. Although they were able to effect the hydrosilylation of ketones, the

BBD’s were only able to impart minor enantioselectivity into the catalytic manifold.

iii

Co-Authorship

I hereby declare that this thesis incorporates material that is the result of a joint research project as follows:

This thesis incorporates the outcome of research undertaken with the assistance of visiting student Ryoto Kojima and postdoctoral research fellow Dr. Patrick Eisenberger. Unless otherwise stated the experimental efforts and data analysis were performed by the author.

I certify that, with the above qualification, this thesis and the research to which it encompasses is the product of my own work.

Acknowledgements

There are many people I need to thank for their contributions to the work presented here, however the greatest debt of gratitude I owe is to my parents, Doug and Valerie Bestvater to whom

I dedicate this document. Without your ceaseless and unconditional support, patience, and love I could not have completed all my years of schooling let alone scale the colossal mountain that this document represents. Thank you for all you have given me.

Amongst the many others to whom I owe my thanks for their guidance during my time here at Queen’s I would first like to thank my supervisor Dr. C. Crudden. Thank you for giving me the opportunity to work in your laboratory, pushing me to accomplish more than I ever thought I could. I have learned a great deal since I began my studies under your guidance. You have given me the opportunity to meet many brilliant scientists, not least amongst them is yourself, and for that I am thankful.

I would also like to thank Dr. Patrick Eisenberger for his guidance and friendship these past years. Patrick, I am still in awe of your mastery of chemistry, both in the laboratory and in your truly awesome command of the literature. Thank you for all you have taught me, allowing me to work with you on your projects, and for all the late night beer sessions despite your insistence on the most revolting, hoppiest IPA in whatever bar we were patronizing.

Lastly I would like to thank the remainder of the Crudden group. From my first days here you guys welcomed me in, everyone was always ready to offer their help in the lab, we had great discussions during our weekly synthesis meetings and our group parties were always something the rest of the department envied. Megan, you are the glue that holds this group together and your assistance and friendship has been very much appreciated these past years. I would like to thank

Chris Ziebenaus, Eric Keske and Sam Voth. There isn’t much I can say except you guys are great, each of you has taught me so much and we had some great times, though they are quite hazy thanks to Sam. I would also like to thank Jason Rygus and Josh Clarke, again both of you guys have been v great friends and I wish you both the best of luck in your future endeavors as well as the rest of the

Crudden Group.

Table of Contents

Abstract ...... ii Co-Authorship ...... iv Acknowledgements ...... v List of Figures ...... ix List of Tables ...... xiii List of Schemes ...... xiv List of Abbreviations ...... xv Chapter 1 Introduction; Lewis Acids and Bases, Boro-cations and their Application to Main- Group Catalysis ...... 1 1.1 Introduction ...... 1 1.2 Lewis Acids and Bases ...... 2 1.2.1 Lewis Acids as Catalysts ...... 3 1.2.2 Lewis Bases as Catalysts ...... 6 1.2.3 Lewis Acids-Base Pairs – Classical Adducts and Steric Frustration ...... 11 1.3 Hydrogenation in Organic Chemistry ...... 11 1.3.1 Transition-Metal Free Hydrogenations and Frustrated Lewis Pairs ...... 13 1.4 Hydrosilylation ...... 24 1.4.1 Metal-Free Hydrosilylations ...... 27 1.5 Boro–Cations ...... 29 1.5.1 Boron Cations as Catalysts ...... 31 1.6 Research Objectives ...... 37 1.7 Thesis Objectives ...... 38 1.8 Chapter 1 References ...... 39 Chapter 2 Investigations into Boro-Ion Catalysis ...... 54 2.1 Mesoionic Carbene-Borenium Ion Catalyzed Hydrogenations ...... 54 2.1.1 Introduction ...... 54 2.1.2 Non-selective MIC-Borenium Ion Hydrogenation Results and Discussion ...... 55 2.1.3 Enantioselective MIC-Borenium Ion Hydrogenation Results and Discussion ...... 64 2.1.4 Investigations into Borenium Ion Catalyzed Amine Racemization ...... 71 2.2 Introduction Boro-Ion Catalyzed Hydrosilylation ...... 74 2.2.1 Mesoionic Carbene-Borenium Ion Catalyzed Hydrosilylation Results and Discussion76 2.2.2 Borohydride Catalyzed Hydrosilylation of Carbonyl Compounds ...... 83

vii

2.3 Chapter 2 References ...... 88 Chapter 3 Future Work and Conclusion ...... 92 3.1 Future Work ...... 92 3.2 Conclusions ...... 93 3.3 Chapter 3 References ...... 94 Chapter 4 Experimental ...... 95 4.1 General Experimental Considerations ...... 95 4.2 Reagents and Materials ...... 95 4.3 Characterization ...... 96 4.4 Synthesis ...... 97 4.4.1 General Procedure for Hydrogenation using MIC-Borenium in an Autoclave (GP1) .. 97 4.4.2 Fenchone Competition Experiment ...... 98 4.4.3 General Procedure for the Synthesis of Carbene-BBDs, Room Temperature (GP2) . 103 4.4.4 General Procedure for the Synthesis of Carbene-BBDs, -78 °C (GP3) ...... 103 4.4.5 BCF Racemization Experiment ...... 104 4.4.6 MIC-Borenium Racemization Experiment ...... 105 4.4.7 General Procedure for the MIC-Borenium Catalyzed Hydrosilylation of Imines (GP4) ...... 106 4.4.8 Borenium Catalyzed Hydrosilylation of 8-Methylquinoline ...... 111 4.4.9 General Procedure for the Borohydride Catalyzed Hydrosilylation of Carbonyl Functionalities (GP5) ...... 113 4.5 Chapter 4 References ...... 116 4.6 Appendix ...... 119

viii

List of Figures

Figure 1-1 Lewis acid-base adduct formation ...... 2 Figure 1-2 General activation by Lewis acids and bases ...... 3 Figure 1-3 General Mukaiyama aldol reaction ...... 3 Figure 1-4 Enantioselective examples of the Mukaiyama aldol reaction ...... 4 Figure 1-5 Oxazaborolidine catalyzed Diels-Alder reaction in Corey et al. synthesis of Eunicenone A ...... 5 Figure 1-6 Sharpless asymmetric epoxidation used in key step in synthesis of (20R)- homocamptothecin ...... 6 Figure 1-7 4-Dimethylaminopyridine-catalyzed acylation of anilines ...... 7 Figure 1-8 Mechanism of pyridine-catalyzed acylation ...... 7 Figure 1-9 Kinetic resolution of alcohols using Fu’s catalyst 1-3 ...... 8 Figure 1-10 Lewis base activation of allylsilanes and silyl enol ethers ...... 9 Figure 1-11 Cesium fluoride mediated allylation with trifluorosilanes with proposed transition state ...... 9 Figure 1-12 Phosphoramide catalyzed asymmetric allylation ...... 10 Figure 1-13 Divergent pathways for allyltrichlorosilanes Lewis base activation ...... 10 Figure 1-14 Linked phosphoramide catalyzed allylation ...... 11 Figure 1-15 Hydrogenation of olefins by Wilkinson’s catalyst ...... 12 Figure 1-16 Pre-FLP transition metal-free hydrogenations ...... 13

Figure 1-17 Synthesis and reversible activation of H2 by a phosphine borane ...... 14 Figure 1-18 Examples of intra- and intermolecular FLPs ...... 16 Figure 1-19 Enantioselective FLP hydrogenation catalysts ...... 18 Figure 1-20 Imine/N-Heterocycle FLP hydrogenation using an added Lewis base ...... 19 Figure 1-21 Imine/N-Heterocycle FLP hydrogenation using an “internal” base ...... 20 Figure 1-22 Dihydrogen splitting by transition metals and Lewis acid/base pairs ...... 21 Figure 1-23 Electric field model for hydrogen splitting ...... 23 Figure 1-24 Orbital interactions in FLP induced dihydrogen splitting ...... 24 Figure 1-25 Hydrosilylation of organic moieties ...... 24 Figure 1-26 Functionalization pathway of vinyl silanes ...... 25 Figure 1-27 Hayashi’s enantioselective hydrosilylation of terminal olefins ...... 26 Figure 1-28 Mechanism of nucleophile catalyzed hydrosilylation ...... 27

Figure 1-29 BCF-catalyzed hydrosilylation mechanism ...... 28 Figure 1-30 Oestreich’s hydrosilylation inversion experiment ...... 29 Figure 1-31 Classes of boron cations and corresponding examples ...... 30 Figure 1-32 Oxazaborolidine (CBS) catalysts ...... 31 Figure 1-33 Valine derived oxazaborolidine ...... 32 Figure 1-34 Catalytic cycle and proposed transition state for CBS reduction ...... 33 Figure 1-35 Proposed catalytic cycle for NHC borenium-catalyzed hydrogenation ...... 35 Figure 1-36 Substrate scope of borenium 1-20 catalyzed reductions ...... 36 Figure 1-37 Proposed meso-ionic carbene borenium catalytic manifold ...... 37 Figure 1-38 The chiral borane, 10-Substituted-[3.3.2]9-borobicyclodecane (BBD) ...... 38 Figure 1-39 Chiral borohydride catalyzed hydrosilylation ...... 38 Figure 2-1 Carbene borane adducts investigated as hydrogenation catalysts. Dipp = 2,6- diisopropylphenyl ...... 55 Figure 2-2 Carbene-borenium ion generation from carbene-borane ...... 56 Figure 2-3 Proposed catalytic cycle and off-cycle equilibrium for MIC-borenium ion catalyzed hydrogenations ...... 60 Figure 2-4 Components of a carbene-borenium ion hydrogenation catalyst ...... 65 Figure 2-5 Unfavorable interactions between MIC and BBD...... 69 Figure 2-6 Masamune Borane 2-24...... 71 Figure 2-7 BCF catalyzed racemization of 2-25 followed by 1H NMR ...... 73 Figure 2-8 1H NMR analysis of borenium ion, 2-3a, catalyzed racemization of 2-25...... 74 Figure 2-9 Proposed mechanism for borenium ion catalyzed hydrosilylation ...... 78 Figure 2-10 Proposed mechanism of borohydride catalyzed carbonyl hydrosilylation ...... 83 Figure 3-1 Proposed MIC-stabilized Masamune borenium ion ...... 92 Figure 4-1 BCF catalyzed racemization of 2-25 followed by 1H NMR ...... 105 Figure 4-2 MIC-boreniun catalyzed racemization of 2-25 followed by 1H NMR ...... 106 1 Figure 4-3 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 20 min ...... 112 1 Figure 4-4 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 1 h ...... 112 1 Figure 4-5 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 18 hr ...... 113 Figure 4-6 Chiral SFC spectra for 2-39b racemate (above) and scalemic (below)...... 114 Figure 4-7 1H NMR of 2-10g ...... 119 x

Figure 4-8 13C NMR of 2-10g ...... 120 Figure 4-9 1H NMR of 2-10h ...... 120 Figure 4-10 13C NMR of 2-10h ...... 121 Figure 4-11 1H NMR of (rac) – 2-16a. Unknown impurities at 7.9 and 8.75 ppm...... 121 Figure 4-12 13C NMR of (rac) – 2-16a ...... 122 Figure 4-13 11B NMR of (rac) – 2-16a ...... 122 Figure 4-14 1H NMR of (rac) – 2-16b ...... 123 Figure 4-15 13C NMR of (rac) – 2-16b ...... 123 Figure 4-16 11B NMR of (rac) – 2-16b ...... 124 Figure 4-17 1H NMR of (S) – 2-18 ...... 124 Figure 4-18 13C NMR of (S) – 2-18 ...... 125 Figure 4-19 11B NMR of (S) – 2-18 ...... 125 Figure 4-20 1H NMR of (rac) – 2-19a ...... 126 Figure 4-21 13C NMR of (rac) – 2-19a ...... 126 Figure 4-22 11B NMR of (rac) – 2-19a ...... 127 Figure 4-23 1H NMR of (rac) – 2-21a ...... 127 Figure 4-24 13C NMR of (rac) – 2-21a ...... 128 Figure 4-25 11B NMR of (rac) – 2-21a ...... 128 Figure 4-26 1H NMR of 2-6h ...... 129 Figure 4-27 13C NMR of 2-6h ...... 129 Figure 4-28 1H NMR of 2-6i ...... 130 Figure 4-29 13C NMR of 2-6i ...... 130 Figure 4-30 1H NMR of 2-6j ...... 131 Figure 4-31 13C NMR of 2-6j ...... 131 Figure 4-32 19F NMR of 2-6j ...... 132 Figure 4-33 1H NMR of 2-6k ...... 132 Figure 4-34 13C NMR of 2-6k ...... 133 Figure 4-35 1H NMR of 2-6l ...... 133 Figure 4-36 13C NMR of 2-6l ...... 134 Figure 4-37 1H NMR of 2-6e ...... 134 Figure 4-38 13C NMR of 2-6e ...... 135 Figure 4-39 1H NMR of 2-6e ...... 135 Figure 4-40 13C NMR of 2-6e ...... 136 Figure 4-41 1H NMR of 2-6m ...... 136 xi

Figure 4-42 13C NMR of 2-6m ...... 137 Figure 4-43 1H NMR of 2-6n ...... 137 Figure 4-44 13C NMR of 2-6n ...... 138 Figure 4-45 1H NMR of 2-6o ...... 138 Figure 4-46 13C NMR of 2-6o ...... 139 Figure 4-47 1H NMR of 2-39a ...... 139 Figure 4-48 13C NMR of 2-39a ...... 140 Figure 4-49 1H NMR of 2-39b ...... 140 Figure 4-50 13C NMR of 2-39b ...... 141 Figure 4-51 1H NMR of 2-39d ...... 141 Figure 4-52 13C NMR of 2-39d ...... 142 Figure 4-53 1H NMR of 2-39e ...... 142 Figure 4-54 13C NMR of 2-39e ...... 143 Figure 4-55 1H NMR of 2-39f ...... 143 Figure 4-56 13C NMR of 2-39f ...... 144 Figure 4-57 1H NMR of (cis) – 2-39g ...... 144 Figure 4-58 13C NMR of (cis) – 2-39g ...... 145 Figure 4-59 1H NMR of (trans) – 2-39g ...... 145 Figure 4-60 13C NMR of (trans) – 2-39g ...... 146

xii

List of Tables

Table 1-1 Metal-free hydrogenations, at 5 mol% 1-8 and 5 atm H2 ...... 15 Table 1-2 Substrate scope of FLP hydrogenations ...... 17 Table 2-1 Borenium ion catalyzed imine hydrogenation optimization...... 57 Table 2-2 Borenium ion 2-3a catalyzed imine hydrogenation...... 59 Table 2-3 Borenium ion 2-3a catalyzed quinoline hydrogenations ...... 62 Table 2-4 Borenium ion 2-3a catalyzed N-heterocycle hydrogenation...... 63 Table 2-5 Attempted synthesis of carbene-9-BBDs ...... 69 Table 2-6 Silane optimization for borenium ion catalyzed hydrosilylation...... 77 Table 2-7 Borenium ion catalyzed imine hydrosilylation substrate scope...... 79 Table 2-8 Borenium ion catalyzed imine hydrosilylation substrate scope...... 80 Table 2-9 Borenium ion catalyzed hydrosilylation of 8-methylquinoline...... 82 Table 2-10 Substrate scope of achiral borohydride catalyzed hydrosilylation ...... 85 Table 2-11 Optimization for BBD borohydride catalyzed hydrosilylation ...... 86 Table 2-12 Condition screening for enantioenriched BBD borohydride catalyzed hydrosilylation ...... 87 Table 4-1 Borenium catalyzed hydrosilylation of 8-methylquinoline...... 111

xiii

List of Schemes

Scheme 2-1 Synthesis of 9-borobicyclo[3.3.2]decanes ...... 66 Scheme 2-2 Synthesis of lithium dihydro-9-borabicyclodecanes ...... 67 Scheme 2-3 Synthesis of MIC-BBDs ...... 68 Scheme 2-4 Stephan’s BCF catalyzed racemization of bis[(R)-1-phenylethyl]amine (24) ...... 71 Scheme 2-5 Previous reports of borenium ion catalyzed hydrosilylation by Jäkle and Denmark (34) (35) ...... 75 Scheme 2-6 Partially reduced quinoline capture by aldehyde...... 82

xiv

List of Abbreviations

9BBN 9-Borabicyclo[3.3.1]nonane

Ac Acetyl-

AN Acceptor Number

Ar Aryl-

BBD 9-Borabicyclo[3.3.2]decane

BCF B(C6F5)3 Tris(pentafluorophenyl)borane

BDE Bond Dissociation Energy

CBS Corey – Bakshi – Shibata

COD 1,5-Cyclooctadiene

Cy Cyclohexyl-

Dipp Diisopropylphenyl

DMAP 4-Dimethylaminopyridine e.e. Enantiomeric excess e.r. Enantiomeric Ratio

HBC Heterolytic Bond cleavage

HOMO Highest Occupied Molecular Orbital

LUMO Lowest Unoccupied Molecular Orbital

Nap 1-Napthyl

NHC N-Heterocyclic Carbene

MIC Mesoionic Carbene

PMHS Polymethylhydrosiloxane

PMP Paramethoxyphenyl

Py Pyridine

THF Tetrahydrofuran xv

Chapter 1

Introduction; Lewis Acids and Bases, Boro-cations and their

Application to Main-Group Catalysis

1.1 Introduction

Since the beginning of the 20th century, the lexicon of reactions from which synthetic chemists can draw upon to stitch together and manipulate organic molecules has grown substantially. Undoubtedly some of the greatest advances have been made with the advent of homogeneous catalysis for redox and coupling reactions through transition-metals. (1) Though advances in this field are on-going, most recently and most excitingly a “renaissance” in main- group chemistry is increasing the tool box chemists may use to manipulate molecules. (2) The early years of the 21st century saw the realization that low oxidation state main-group compounds can possess electronic properties and frontier orbitals similar to those of transition metals allowing them to engage in bond-activation chemistry. (3) This led to the development of the concept of frustrated

Lewis pair (FLP) catalysis, an expansion of the well-established concept of Lewis acid and base catalysis. (3) This form of catalysis has promise in regards to small molecule activation, particularly hydrogenation, revealing the possibility of moving beyond expensive and often toxic transition- metals to relatively benign and cheap main-group elements. (4) The further expansion and investigation of the emerging field of FLP-chemistry in order to increase catalyst activity, robustness, and allow for greater chemo- and stereocontrol of reactants is the goal of the work described in this thesis.

1.2 Lewis Acids and Bases

The concept of atoms being able to donate or accept electron pairs was first put forth by

Gilbert Lewis in 1923. (5) Since then his model has become one of the most foundational concepts in chemistry helping to rationalize the reactivity of an endless variety of molecules. In his model,

Lewis described all bonding as simply interactions between electron-rich and electron-poor species, using what he referred to as the “rule of two”. (6) Inother words, Lewis bases are electron-pair donors and Lewis acids are electron-pair acceptors. Fundamentally this definition is based on the need for atoms to have a filled outer shell of electrons and the assumption that this occurs when an atom is in its most stable state. (7) In terms of orbital interactions, Lewis acids are species possessing a (relatively) energetically low lying LUMO whereas Lewis bases are species possessing a (relatively) energetically high energy HOMO. (6) The proto-typical example of this interaction is the adduct formed between borane and trimethylamine (Figure 1-1). (8)

Figure 1-1 Lewis acid-base adduct formation

In this example, ammonia as the Lewis base donates its electron pair to the empty p-orbital on boron acting as the Lewis acid. The interaction of these two species induces a redistribution of electron density in both the acceptor and donor fragments, resulting in a pronounced change in geometry and reactivity of the adduct. (9) (7) The ability to redistribute the electron density of molecules allows chemists to tune the reactivity of molecules in two ways; 1) the increase of the electrophilicity of molecules by complexation to a Lewis acid or 2) increase of nucleophilicity of molecules by complexation to a Lewis base (Figure 1-2). (7)

Figure 1-2 General activation by Lewis acids and bases

This simple concept has allowed chemists to logically design new catalysts to modulate the reactivity of various compounds and control the reactivity. In addition, the use of Lewis acid or bases as catalysts affords the opportunity for chemists to introduce asymmetry into otherwise non- selective reaction manifolds and produce enantiomerically enriched compounds with greater efficiency. (10) (7) A brief overview of how Lewis acids and bases are used with examples is given in the next section.

1.2.1 Lewis Acids as Catalysts A prototypical example for Lewis acids ability to increase substrate reactivity, is their interaction with carbonyl species resulting in increased bond polarization, for example in the

Mukaiyama aldol reaction. Developed in the 1970's by Teruaki Mukaiyama, the Lewis acid catalyzed reaction is a modification of the well-known aldol reaction utilizing silyl enol ethers as trapped enolates, which are induced to nucleophilically attack carbonyl compounds by a Lewis acid, Figure 1-3. (11) (12) (13) (14) (15) (16)

Figure 1-3 General Mukaiyama aldol reaction

Since the seminal publications first outlining the Mukaiyama aldol, much effort has been devoted to the development of catalysts allowing for the stereocontrol of the reaction. Given that

this reaction proceeds without coordination between the reacting partners, otherwise known as an open transition state, the development of enantioselective catalysts for the Mukaiyama aldol has been a difficult task. (17) Thus far Sn(II) and Ti(IV) based catalysts have been the most successful.

(13) (15) Kobayashi and Mukaiyama developed one of the first highly selective catalyst systems, utilizing Sn(OTf)2 and a proline derived diamine ligand. (12) With this they were able to achieve good to excellent e.e.’s (78 – 98 %) in moderate yields (52 – 91 %) for the addition of silyl enol ethers to aldehydes. (12) Carreira et al. introduced another highly successful titanium-based catalyst using a BINOL derived Schiff-base ligand (1-2), Figure 1-4. (15)

Figure 1-4 Enantioselective examples of the Mukaiyama aldol reaction

Other examples of Lewis acids being used to control reactivity include cycloaddition type reactions, including the Diels-Alder reaction. One of the most successful classes of Lewis acid thus far developed to catalyze the Diels-Alder reaction are the oxazaborolidines. Extensively investigated

by the labs of E. J. Corey, oxazaborolidines catalyze the Diels-Alder reaction with excellent control over diastero- and enantioselectivity. (17) (18) (19) An example demonstrating this selectivity was shown by Corey et al. in their synthesis of Eunicenone A, the key step installing the molecules stereochemistry using an oxazaborolidine catalyst in a Diels-Alder cycloaddition, Figure 1-5. (20)

Furthermore, oxazaborolidines have also been heavily investigated as enantioselective catalysts for carbonyl reductions in the Corey-Bakshi-Shibata reaction, which will be discussed in section 1.5.1.

(21)

Figure 1-5 Oxazaborolidine catalyzed Diels-Alder reaction in Corey et al. synthesis of Eunicenone A

As a final example demonstrating the utility of Lewis acids is seen in the example of

Sharpless asymmetric epoxidation (SAE). The first practical method for the asymmetric epoxidation of allylic alcohols, (22) the SAE utilizes a Ti(IV)-diethyl-tartrate catalyst to coordinate a tert-butyl hydroperoxide and direct it selectively to a particular face of a pro-chiral allylic alcohol.

(23) Since its development, the SAE has become an indispensable tool for organic synthesis used in a variety of total synthesis. (24) (25) (26) As an example, the labs of Curran used the SAE to install the key stereochemistry in their total syntheses of (20R)-homocamptothecin, Figure 1-6 (27)

Figure 1-6 Sharpless asymmetric epoxidation used in key step in synthesis of (20R)- homocamptothecin

Other examples of Lewis acids used in synthesis include the Luche reduction, Mannich reaction, variants of the aldol etc. (28) Overall, all these reactions are based on the same principle of modulating the reactivity of molecules in order to control the selectivity of a reaction, and have been used in a huge variety of ways. (10)

1.2.2 Lewis Bases as Catalysts Lewis base catalysis, although less common than Lewis acid catalysis, can also be employed in important organic transformations. (7) Key interactions found in Lewis base catalysis can be divided into three classes as proposed by Jensen (6): 1) non-bonding electron pairs interacting with anti-bonding π-orbitals (n-π* interactions), 2) non-bonding electron pairs with anti- bonding σ-orbitals (n-σ* interactions), and 3) non-bonding electron pairs with anti-bonding n- orbitals (n-n* interactions). (9) Examples of these forms of catalysis are given below.

One of the best known examples of n-π* Lewis base catalysis is the use of 4- dimethylaminopyridine (DMAP), and its derivatives to catalyze the acylation of alcohols, amines and thiols, Figure 1-7. DMAP catalyzed acylations were first demonstrated by Kirichenko (29) and subsequently by Steglich (30), both of whom showed that DMAP greatly enhanced the reactions rates of acylation over previously used pyridine. (31)

Figure 1-7 4-Dimethylaminopyridine-catalyzed acylation of anilines

Prior to the work of Kirichenko (29) and Steglich (30) the Lewis base required for acylations was thought to be acting solely as a Brønsted base to sequester the protons produced in the reaction. (32) This was found to be incorrect, and rather it was shown that the pyridine acts catalytically as shown below, Figure 1-8. The pyridine nitrogen attacks the acyl donor (the n-π* interaction) forming N-acylpyridinium ion II. The acyl donor is now highly electrophilic and is subsequently attacked by the nucleophile producing intermediate III, which upon deprotonation yields product IV (32) (33)

Figure 1-8 Mechanism of pyridine-catalyzed acylation

Enantioselective examples of this transformation were subsequently developed, allowing for the resolution of racemic of alcohols, amines, and thiols by selective acylation. One of the most well-known being the variant developed by Fu and co-workers utilizing 1-3, a chiral DMAP derivative. Figure 1-9, (34) (35) (36) (37)

Figure 1-9 Kinetic resolution of alcohols using Fu’s catalyst 1-3

The largest drawback to this system is a theoretical maximum yield of 50% when starting from racemic alcohols. Most recently this has been significantly improved upon by Fu and co-workers by the introduction of a secondary ruthenium catalyst that is capable of racemizing the unreacted alcohol, turning the process into a dynamic kinetic resolution, allowing for the quantitative enantioconvergent acylation of racemic alcohols. (38)

Lewis bases have also been extensively investigated as catalysts for the activation of silicon containing molecules. It has been known for some time that silicon is able to expand its coordination sphere beyond the usual octet of electrons and form stable penta- and hexacoordinate species, which was taken advantage of, for the Lewis base catalysis in the case of allylation and aldol reaction. (39) (40) This is an example of n-σ* Lewis base catalysis. The coordination of a

Lewis base to a silane results in a redistribution of electron density away from the silicon atom, rendering it more electrophilic/Lewis acidic, whilst simultaneously making the silicon’s ligands more electron rich, sometimes referred to as “spill-over”. (41) Ultimately, this leads to an increase in the nucleophilicity of the silane substituents. (42) The dual activation of silanes has been used to great effect for the activation of allylsilanes (43) and silyl enol ethers (44) (7), increasing the nucleophilicity of the gamma position to allow for the addition to carbonyl compounds, Figure

1-10.

Figure 1-10 Lewis base activation of allylsilanes and silyl enol ethers

Depending on the substituents on silicon, these reactions can proceed in a variety of different ways. (43) In the case of allyltrialkylsilanes, addition of a Lewis base causes complete dissociation of the allyl fragment rendering nucleophilic attack unselective. (45) (46) (47) In the case of trialkyloxysilyl enol ethers, complete dissociation of the enolate ion does not occur and addition to electrophiles tends to occur via an open transition state. This has the unfortunate result of making the addition of trialkylsilyl enol ethers to carbonyls diastereoconvergent and as well as making high enantioselectivities difficult to achieve. (48) (49) (50) (7) As a result, electron-poor silanes that would not release a free allyl anion and be able to coordinate the carbonyl electrophile favoring a closed transition state, were investigated. Sakurai et al. first demonstrated this in fluoride ion mediated crotylations with (E)- and (Z)- crotyltrifluotosilane, which proceeded with excellent diastereoselectivity, Figure 1-11. (51) (52) (42)

Figure 1-11 Cesium fluoride mediated allylation with trifluorosilanes with proposed transition state 9

Following others work (53) (54), in 1994, Denmark demonstrated the first enantioselective Lewis base catalyzed allylation using a chiral phosphoramide 1-4, Figure 1-12. (55)

Figure 1-12 Phosphoramide catalyzed asymmetric allylation

Investigations into other catalysts and the mechanism of the reaction in order to improve the enantioselectivity revealed the reaction has two operative pathways, one in which the trichlorosilane is monoligated by the catalyst and another where the trichlorosilane is bis-ligated.

The latter pathway resulting in improved enantioselectivities for the allylation reaction, Figure

1-13. (56) (57) (7)

Figure 1-13 Divergent pathways for allyltrichlorosilanes Lewis base activation

The insight of divergent reaction pathways lead to the development of linked dimeric phosphoramides, such as 1-4 (Figure 1-14), in order to favor the bis-ligated pathway over the monoligated pathway. The bidentate catalyst motif proved to be an effective approach as

demonstrated in catalyst 1-5, which showed a marked increase in enantioselectivity as compared to the simple phosphoramides. (58)

Figure 1-14 Linked phosphoramide catalyzed allylation

The case of Lewis base catalyzed allylation and aldol reactions is an excellent example of how the careful analysis and understanding of reaction mechanisms is a requirement for the development of highly selective catalysts. A final example of n-n* Lewis base catalysis is given in section 1.51.

1.2.3 Lewis Acids-Base Pairs – Classical Adducts and Steric Frustration One of the most interesting developments in Lewis acid/base catalysis is the joining of both modes of action into a single catalytic principle in what is now termed frustrated Lewis Pairs

(FLPs). (59) By choosing Lewis acids and bases that are bulky, enables them to work in concert in the activation of small molecules in novel catalytic manifolds. This has been most successfully applied to the activation of dihydrogen towards the developments of metal-free hydrogenation catalysts. This will be discussed more in-depth in section 1.3.1.

1.3 Hydrogenation in Organic Chemistry

The catalytic addition of molecular hydrogen across multiple bonds is one of the oldest and most fundamental reactions in organic chemistry and one of the most extensively studied. (1) As such, an in-depth review on this topic is beyond the scope of this thesis and only a brief overview of the field will be given, in order to gain some perspective and provide the backdrop for a more in-depth discussion of metal-free/FLP type hydrogenations.

The high bond strength of molecular hydrogen, as indicated by its high bond dissociation energy, 104.2 kcal/mol and energy of heterolytic bond cleavage, 128.8 kcal/mol, (60) necessitates the use of catalysts in order to break the dihydrogen bond and employ it in chemical reactions.

Catalysts that activate dihydrogen can be broadly put into two categories; heterogeneous and homogeneous, referring to whether or not the catalyst is soluble in the reaction medium. In either case, the catalysts are mostly based on late transition metals, typically Ru, Rh, Ir, Pd, Pt, Cu, however, examples of early transition metal based catalysts have been reported. (1) Heterogeneous hydrogenation catalysts, mostly developed in the early 20th century, include catalysts such as Raney nickel (61) and Adam’s catalysts (PtO2) to name two well-known examples. (62) In the 1960's and

1970's, the field of homogenous catalysis began to rapidly develop with the discovery of highly catalytically active metal complexes such as Wilkinson’s (Rh(PPh3)Cl) (63), and Crabtree’s

([Ir(COD)(Py)PCy3]BF4) catalyst. (64) These early studies largely focused on the hydrogenation of carbon – carbon multiple bonds and for this they proved especially well suited, and able to reduce a wide range of olefins.

Figure 1-15 Hydrogenation of olefins by Wilkinson’s catalyst

As opposed to the hydrogenation of carbon-carbon multiple bonds, the hydrogenation or reduction of carbon – heteroatom multiple bonds, has, for the large part been the realm of metal hydrides (e.g. NaBH4 and LiAlH4) and heterogeneous catalysts (e.g. Pd/C and Pt/C) (1). However, both of these methods have significant drawbacks. Metal hydrides, permit good chemo- and stereocontrol, but suffer from poor atom economy in comparison to metal catalyzed hydrogenations 12

and require the laborious removal of boron or aluminum byproducts, both these factors combined make them poorly suited for large industrial scale reactions. In addition, the reagents can react violently. Heterogeneous methods have good atom economy but are less applicable where greater functional group tolerance and milder reaction conditions are required. (65)

1.3.1 Transition-Metal Free Hydrogenations and Frustrated Lewis Pairs Prior to the development of frustrated Lewis pairs (FLPs), no systems were known to reversibly bind hydrogen other than transition metal complexes and there were only scattered examples of transition-metal free systems known to catalyze hydrogenations. (59) Of these, most required extremely forcing conditions, either needing high temperatures (> 200 °C), (66) pressures

(170 atm) (67) or exceptionally acidic conditions utilizing superacids (HF-SbF5) severely limiting their broad applicability. (68)

Figure 1-16 Pre-FLP transition metal-free hydrogenations

As such, the 2006 Stephan report of the first reversible, metal-free activation of dihydrogen

(69) was met with considerable interest. In subsequent work, the Stephan group showed that this same systems could catalyze the addition of hydrogen to imines under much milder conditions than those previously observed. (70) During their studies on phosphine-borane interactions, Stephan et al. found that the combination of tris(pentafluorophenyl)borane (BCF), 1-5, and dimesitylphosphine rather than producing a Lewis adduct underwent a nucleophilic aromatic

substitution producing the zwitterionic species 1-6. By treatment with Me2SiHCl, it was possible to produce borohydride species 1-7 by fluoride-hydride exchange. Remarkably, compound 1-7 proved to be quite stable despite possessing both acidic and hydric moieties and was shown to be both air- and moisture-stable. However, upon heating to temperatures above 100 °C 1-7 was shown to liberate dihydrogen producing 1-8, which upon treatment with as little as 1 atm of dihydrogen resulted in the clean reformation of 1-7. Thus Stephan et al. had discovered metal-free systems capable of reversible activation/heterolytic cleavage of dihydrogen. (69)

Figure 1-17 Synthesis and reversible activation of H2 by a phosphine borane

Subsequently, Stephan et al. showed that 1-8 could catalyze the hydrogenation of imines, aziridines , and BCF-protected nitriles under conditions much milder than those previously reported for metal-free systems,

Table 1-1. Electron-rich and electron-poor imines were both cleanly reduced (entries 1 and 2), albeit the latter after longer reaction times. This indicated that the basicity of the nitrogen plays a significant role in the rate of the reaction, most-likely as a result of diminished rates of proton transfer from the P-centre to the N-centre of the substrate. Furthermore, imines with decreased steric bulk around the N-centre severely retarded the ability of 1-8 to catalyze hydrogenation due

to the formation of amine-borane adducts, limiting turnover to only stoichiometric reduction (entry

3 vs. 4). Similarly, in the case of the hydrogenation of nitriles, protection of the nitrogen by first coordination with BCF (entry 5) was required to prevent coordination to 1-8 and allow for catalytic turnover. Finally, 1-8 was also able to catalyze the hydrogenation of aziridines leading to the ring- opened product (entry 6). (70)

Table 1-1 Metal-free hydrogenations, at 5 mol% 1-8 and 5 atm H2

With these seminal publications, as well as the realization that earlier work conducted by

Piers’s et al. on BCF catalyzed hydrosilylations also function by a similar mechanism to FLP activation, (71) the field of FLP chemistry began to expand rapidly. Subsequent publications reported new catalytic manifolds, including intra- (72) (73) (74) and intermolecular (75) (76) (77)

(78) FLPs, capable of hydrogenations, at lower temperatures, pressures, and catalyst loadings

Figure 1-18.

Figure 1-18 Examples of intra- and intermolecular FLPs

Thus far, the majority of FLP hydrogenation catalysts reported have largely employed perfluorinated aryl boranes, either as BCF alone or connected via a tether to a phosphorus or nitrogen centre, Figure 1-18. Aluminum, (79) silicon, (80) (81) carbon (82) (83), and phosphorus

(84) based Lewis acids have also been investigated for their use in FLP manifolds, though they have met little success as hydrogenation catalysts. However, cationic boron species, which due to their positive charge negate the need for highly electron-withdrawing perfluorinated substituents on the boron, have been successfully applied as FLP hydrogenation catalysts, see section 1.5.1.

Finally carbenes have been also been investigated as Lewis bases (85) (86) in FLP systems, though not successfully as hydrogenation catalysts.

One interesting modification on the FLP concept has been the realization that addition of a bulky Lewis base is not always needed and it is possible to use an “internal” base such as an imine or N-heterocycle in combination with a strong Lewis acid such as BCF to effect hydrogen splitting.

This notion was exploited independently by Stephan and Klankermayer for the reduction of bulky imines and N-heterocycles. (87) (88) (89) Overall these developments have vastly expanded the 16

scope of substrates (see Table 1-2) capable of being reduced by FLP manifolds including; silylenol ethers, (75) disubstituted alkynes, (90) 1,1-disubstituted alkenes, (76) activated alkenes, (78) (91) and heteroaromatics. (92) It should also be noted that FLPs have also been investigated for their reactivity with a variety of other small molecules including; CO, (93) CO2, (94) N2O, (95) NO, (96)

SO2, (97) and RNSO. (98)

Table 1-2 Substrate scope of FLP hydrogenations

In addition to the investigation of new catalysts and the broadening of substrate scope, significant interest has been directed towards enantioselective FLP hydrogenations. Thus far, the development of chiral perfluoroaryl-containing boron-centered Lewis acids has been the main focus, given that hydride delivery is most likely the stereo-defining step. (99) Some initial investigations have, however, assessed the applicability of using chiral phosphine and amine Lewis bases for enantioselective hydrogenations but only poor to moderate enantioselectivities (6 – 37 % e.e.) have been achieved for the hydrogenation of imines. (100) (101) The first enantioselective

FLP hydrogenation catalyst capable of relatively high selectivity (79-83% ee) was reported in 2010 by Klankermayer et al. and utilized a camphor-derived perfluorinated borane as the catalyst for the reduction of prochiral imines. (102) More recent developments have looked into using axial chiral 17

binaphthyl-derived catalysts and have been shown to be capable of similar to superior enantioselectivities than the catalyst previously reported by Klankermayer, Figure 1-19. (103)

(104)

Figure 1-19 Enantioselective FLP hydrogenation catalysts

The proposed mechanism by which the hydrogenation of imines and N-heterocycles proceeds is presented in Figure 1-20 and Figure 1-21. Whether an added or “internal” Lewis base is used, the first step of an FLP hydrogenation is generally the splitting of dihydrogen. The mechanism of this has been investigated computationally at length by the groups of Papai and

Grimme, (105) (106) (107) (108) who have arrived at differing models, which will be discussed more in-depth below. Both groups though do come to the conclusion that the Lewis acid and base components act in concert in an “encounter complex” where the Lewis acidity/basicity is not quenched by each other but rather both catalyst components are capable of interaction with dihydrogen resulting in its heterolytic cleavage into a proton and hydride. This activation step is then followed by proton transfer from the Lewis base to the nitrogen centre when using an added

Lewis base, Figure 1-20. This view is supported by the observed increased reaction times required for more electron-deficient imines when using an added Lewis base, presumably due to the decreased basicity. This is further supported by the inability of tetraphenylphosphonium- borohydrides to reduce imines, showing that protonation is required prior to reduction. (70) 18

Moreover, in the case of using solely BCF to catalyze the reduction of electron-poor imines, the rate of hydrogenation can be increased by the addition of a bulky electron-rich Lewis base such as

P(Mes)3. (87) Following protonation of the imine, hydride transfer is allowed to proceed, generating an amine-borane adduct with the Lewis acidic borane catalyst. The amine must then subsequently dissociate, regenerating the free Lewis acid, permitting the cycle to continue.

Figure 1-20 Imine/N-Heterocycle FLP hydrogenation using an added Lewis base

Figure 1-21 Imine/N-Heterocycle FLP hydrogenation using an “internal” base

Thus far, three basic mechanisms have been proposed for the splitting of dihydrogen by

FLPs. The first two are stepwise, wherein one half of the Lewis pair first coordinates dihydrogen followed by the other half of the Lewis pair attacking the complex and either accepting a hydride or proton, Eq. 1-1 and Eq. 1-2. (77)

Eq. 1-1

Eq. 1-2

In the mechanism shown in Eq. 1-1, dihydrogen first coordinates to the Lewis acid in a side-on fashion followed by the nucleophilic attack of the Lewis base, splitting hydrogen. This is analogous to hydrogen activation by transition metal complexes, which proceeds via formation of a

dihydrogen σ-complex followed by the insertion or oxidative addition of the metal into the H–H bond. (109)

Figure 1-22 Dihydrogen splitting by transition metals and Lewis acid/base pairs

In the first case, the transition metal can be considered as combining both the Lewis acidic and basic centres, donating an electron pair to a proton and accepting a hydride. In an FLP system, the acceptor and donor centers are separated. This mechanism is relatively intuitive given the precedent of such interactions found in transition-metal chemistry, however so far all attempts at direct observation of such σ-complexes with main group Lewis acids and -bases has failed. (60) However, some indirect evidence for such complexes has been provided by Wang et al. In their 2011 study, they showed by isotopic labeling that the electron deficient borane B-D-bis(2,4,6- tris(trifluoromethyl)-borane was capable of undergoing exchange with dihydrogen, replacing the boron deuteride with a hydride in the absence of a Lewis base, indicative of some coordination complex capable of undergoing bond-to-bond exchange. (110) Additionally the formation of Lewis acid sigma-complexes has also been supported by DFT calculations from several authors. (111)

(112) The second postulated pathway, by which the Lewis base coordination occurs first (Eq. 1-2), has garnered little support. Due to a lack of spectroscopic evidence and in silico studies demonstrating repulsive interactions for the end-on approach between dihydrogen and Lewis bases.

(105)

The third pathway for the splitting of hydrogen by FLPs involves a concerted action of the

Lewis pair for the splitting of hydrogen. In this proposed mechanism the Lewis pair form what has

come to be referred to as “frustrated” or “encounter” complex. A loosely interacting complex, held largely together by secondary interactions such as C–H∙∙∙F–C hydrogen bonds, while the Lewis acidic and basic centres remain unquenched. Due to being loosely held together, it is speculated that dihydrogen is able to easily enter this encounter complex and interact with the donor/acceptor centers which are pre-organized for the simultaneous interaction with dihydrogen Eq. 1-3. (105)

Eq. 1-3

This mechanism has thus far garnered the largest amount of support, however, the mode of action by which dihydrogen splitting proceeds has since become a matter of contention with two different models having arisen to explain this. The first model proposed by Pápai et al. in 2008 is referred to as the electron transfer (ET) model and accounts for hydrogen splitting by the synergistic action of both Lewis acidic and basic centres. More specifically a lone pair from a Lewis base is donated to the σ*(H2) orbital and a Lewis acid accepts electrons from the σ(H2) orbital. The synergistic action of both the acid and base induce a polarization of the H–H bond leading to its heterolytic splitting in analogy to the splitting of dihydrogen by transition metals previously described, vide supra. (105) The second model proposed by Grimme et al. in 2010, referred to as the electric field (EF) model, suggests that the formation of the encounter complex creates a

“cavity” with a strong electric field that can induce bond polarization leading to the heterolytic cleavage of dihydrogen in a barrierless process. In their initial paper, they showed that an EF of

~0.1 a.u. (1 a.u. = 5.1422x1011 V/m) was sufficiently strong to allow for such splitting of dihydrogen. They thus proposed that any observed reaction barriers are mainly due to the formation of the encounter complex and the entrance of dihydrogen into its cavity. (108) This model deviates significantly from the generally accepted mode of thought used to explain chemical reactivity with its high reliance on orbital interactions and represents a completely novel form of reactivity. If shown to be true, this would make FLP type reactivity unlike anything previously described and

provoked the question as to whether or not previous explanations of hydrogen activation needed reexamination. (107)

Figure 1-23 Electric field model for hydrogen splitting

In a follow-up to their initial paper, Pápai et al. in 2013 elegantly showed using six different

FLP systems that the electric field produced by an FLP encounter complex is insufficient to account for the splitting of hydrogen. It was shown that the EF made in various FLPs are quite inhomogeneous, did not align with the H–H bond as would be expected, and possessed no discernable “cavity” with an EF > 0.1 a.u. Moreover, Pápai et al. found computationally that dihydrogen coordinated within the encounter complex in end-on fashion with the LB (not deviating significantly from 180°) and with a side-on fashion with the LA (typically had an angle of 90 –

120°) resulting in a μ-(η1, η2) transition state complex. This conflicts with the EF model where dihydrogen coordination would be expected to be linear with the H–H bond axis. Furthermore, this bonding mode is as expected with a simple qualitative molecular orbital analysis and closely mirrors what happens in transition metal chemistry. Lastly, calculated intrinsic reaction coordinates

(IRC) showed that only later in the reaction, after the transition state and where dihydrogen had a bond order of ~0.5, was hydrogen exposed to an electric field of >0.1 a.u. and at this point, only the hydrogen atom associated with the LA was exposed to such a high electric field. Overall these finding suggest that the EF model provides predictions in contrast to various computed features observed and that the observed reactivity of FLPs can be explained using a concerted model as analogously to similar chemistry found in transition metal systems. (107)

Figure 1-24 Orbital interactions in FLP induced dihydrogen splitting

1.4 Hydrosilylation

An attractive alternative to using dihydrogen for the reduction of organic compounds is the use of silanes for the hydrosilylation of unsaturated moieties, Figure 1-25. Silanes, as compared to dihydrogen, are safer and easier to handle, are relatively air and moisture stable, and are cheap and relatively abundant as industrial byproducts. (113) (114) (115) (116) Additionally, the hydrosilylation product may either be further functionalized at the site of silane incorporation or be hydrolyzed to formally generate the hydrogenation product. The hydrosilation reaction has been a favorite of organometallic chemists who have developed the reaction for the reduction of carbon- carbon, and carbon-heteroatom multiple bonds and has been applied to the areas of organic synthesis, polymer chemistry and material science. (117) (116) The first example of a hydrosilylation reaction described using a homogeneous catalyst was reported in 1957 using hexachloroplatinic acid. (118) Since then, catalysts have been developed making use of every late transition metal (Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au), many early transition-metals, lanthanides, actinides, and various nonmetals, as well radical initiated variants of the hydrosilylation reaction have been developed. (117)

Figure 1-25 Hydrosilylation of organic moieties

Olefin hydrosilylation generally proceeds with anti-Markovnikov selectivity, with internal acyclic-alkenes generally resulting in the silane at a terminal position. (119) The hydrosilylation of alkynes generally proceeds in a syn-fashion, with the use of Pt based catalysts and in an anti-fashion with the use of Rh, (120) or Ir-based catalysts (121). An attractive aspect of the hydrosilylation reaction is the potential for further manipulation of the resulting product in a variety of other chemical processes, Figure 1-26.

Figure 1-26 Functionalization pathway of vinyl silanes

Like hydrogenation, considerable effort has been directed towards the development of enantioselective hydrosilylation catalysts. The major obstacle to this goal is the tendency of hydrosilylation to proceed with anti-Markovnikov selectivity, resulting in linear achiral silanes. So far the use of palladium based catalysts, which favor branched addition to olefins, using monodentate axial chiral ligands developed by Hayashi et al. have been the most successful approach in overcoming this obstacle, achieve excellent enantioselectivies (90 – 97 % e.e.) for the hydrosilylation of terminal olefins, Figure 1-27. (122) (123) (124) (125) (126)

Figure 1-27 Hayashi’s enantioselective hydrosilylation of terminal olefins

Like the hydrosilylation of carbon-carbon double bonds, much investigation has been directed towards the development of homogeneous metal catalysts for the hydrosilylation carbon- heteroatom multiple bonds. (117) Thus far rhodium(I) catalysts have been the most successful towards the hydrosilylation of carbonyl compounds, starting first with the report by Ojima et al. in

1972 of Wilkinson’s catalyst being a highly active hydrosilylation catalyst. (127) Since then, much like hydrogenation, considerable effort has been directed towards the development of chiral ligands to develop enantioselective hydrosilylation catalysts. (117) Early efforts focused on chelating nitrogen-based ligands, such as PYBOX (128) and sparteiene (129), however these proved suboptimal resulting in only moderate enantioselectivities. (117) Subsequently bidentate phosphine ligands possessing a large bite angles, such as trans-chelating chiral diphosphine (TRAP), were found to be well suited for enantioselective carbonyl hydrosilylation. (130)

Since these reports little improvement has been achieved over these ligands, P,N-bidentate ligands have been shown to be capable of similar levels of enantioselectivity as TRAP ligands while the field has continued to rely largely on rhodium, with group 10 metals play a marginal role. (117)

Of note however, is the development of zinc(II) based catalytic systems utilizing C2 symmetric diamine or diamine ligands with polymethylhydrosiloxane (PMHS) as the hydride donor, which are capable of moderate to good enantioselectivities (51-91%) for the hydrosilylation of aryl

ketones. (131) (132) (133) As with hydrogenation, again some of the most interesting developments in the field of hydrosilylation in the past 20 years has been the development on main-group or metal-free catalysts, which will be discussed in the next section

1.4.1 Metal-Free Hydrosilylations In a similar fashion to hydrogenations and the advent of FLP catalysts, recent years have seen the development of metal-free catalysts for hydrosilylations, utilizing main group elements.

(117) In general, these catalysts can be divided into two classes; nucleophilic/Lewis basic catalysts and Lewis acidic/electrophilic catalysts. Nucleophilic catalysts make use of alkoxides (134) (135) or metal/ammonium fluorides and have been shown to successfully reduce aldehydes, ketones, and imines. (136) (137) (138) Nucleophilic hydrosilylation catalysts act by coordination to the silicon atom, forming a pentacoordinate silane, activating it for hydride delivery. Hydride delivery is generally believed to occur by a hexacoordinate transition state with the electrophile coordinated to the silane, Figure 1-28. (137)

Figure 1-28 Mechanism of nucleophile catalyzed hydrosilylation

Metal-free electrophilic hydrosilylation catalysis was first reported by Piers et al. in 1996.

(139) In their seminal report, Piers et al. found that BCF was a highly active catalyst for the hydrosilylation of aromatic aldehydes, ketones, imines. (71) (140) Recently, this was expanded to

N-heterocycles by Chang et al. who showed that BCF was an effective catalyst for the complete reduction of the nitrogen containing ring in quinolones. (141) Initially it was believed BCF worked by Lewis acid activation of the carbonyl, however, paradoxically it was observed that less basic carbonyls had a higher reaction rate and in competition experiments between different carbonyl-

containing molecules, more basic substrates were reduced selectively. This led the authors to propose that BCF formed a sigma complex with the silane and abstracted a hydride after carbonyl coordination to the silane. The borohydride species then subsequently reduces the activated carbonyl regenerating BCF and forming silyl ether product, Figure 1-29. (139) (71)

Figure 1-29 BCF-catalyzed hydrosilylation mechanism

This reaction mechanism has been supported by various kinetic, competition, labeling, and crossover experiment by Piers et al. in their 2000 paper. (71) Furthermore Oestreich et al. has provided further evidence for this mechanism showing that a chiral-at-silicon silane adds to carbonyls with inversion at silicon when using a BCF catalyst, as would be expected if the above mechanism is operative. (142)

Figure 1-30 Oestreich’s hydrosilylation inversion experiment

Finally, reported by Piers et al. in 2014, the proposed sigma-complex intermediate has been subsequently confirmed by low temperature NMR and x-ray crystallography using a highly Lewis acid borol. (143) Enantioselective variants of metal-free hydrosilylation catalysts have been considerably less investigated. Some reports have looked into using chiral alkoxides (144) (145) and amides derived from amino acids, (146) (147) which have been able to achieve good selectivities but few examples have been reported using chiral main-group Lewis acids, which is surprising given the success they have had for FLP hydrogenations. (117)

1.5 Boro–Cations

Group 13 elements occupy a unique position on the periodic table, possessing only three valence electrons. Group 13 compounds are unable to satisfy their octet as neutral 3-coordinate molecules and are left with a vacant p-orbital still able to accept an electron pair. As a result, these elements have an “intrinsic” electron deficiency. This manifests in the Lewis acidity that characterizes the reactivity of the group 13 elements, and results in their propensity to bond/react in ways that saturate their coordination sphere to satisfy this electron deficiency. Correspondingly, the study of group 13 elements has largely been confined to their neutral and anionic forms.

However, in more recent years cationic species are being investigated as well, unsurprisingly significant interest has been directed towards boron cations. (148) This is chiefly due to their pronounced electron deficiency, resulting in substantial Lewis acidity, thus making them exceptional targets to investigate as catalysts. (149) (150)

In 1985 Nö th et. al. defined the now widely used nomenclature for boron cations, separating them into three distinct classes based on the coordination number of the boron atom,

Figure 1-31. (149) (151) (152) (153)

Figure 1-31 Classes of boron cations and corresponding examples

Borinium cations are two-coordinate species, typically containing two bulky π-donating ligands covalently bound to the boron atom, sterically encumbering the boron atom, and relieving its electron deficiency resulting in considerable sp-hybridized character at the boron.

Unsurprisingly, these species are highly reactive making their study in the condensed phase extremely difficult. Borenium cations are three-coordinate species, possessing two covalently bound substituents on the boron with the third coordination site occupied by some σ-donating ligand. The third class of borocations are boronium ions, which are four-coordinate tetrahedral species with two covalently bound substituents and the other two coordination sites occupied by two σ-donating ligands. Boronium ions, possessing a fully saturated coordination sphere, have the highest stability of the borocations. (148) (149) (150)

In the context of catalysis, in order for any molecule to be useful, it must be able to incorporate new ligands/molecules so that they can be activated and be able release/exchange said 30

ligands so that the catalyst may be regenerated. This obviously makes borinium ions poor candidates for use in some catalytic manifold due to their extreme electron deficit, making them unlikely to be able to release/exchange any substrate once bound. Conversely boronium ions are not able to interact with any substrate without first dissociation of one of its stabilizing ligands.

Borenium ions, however, possess the best of both worlds; an open coordination site, coupled with a high degree of electron deficiency, allowing it to coordinate and activate substrates but still possessing high enough stability to allow for the exchange/release of ligands so that they can function in a catalytic cycle. Some examples of boron cations in catalysis will be shown in the next section

1.5.1 Boron Cations as Catalysts Undoubtedly one of the most well-known and synthetically useful examples of borenium catalysts are the amino alcohols derived oxazaborolidines, see 1-12a–c for examples. These boreniums have proven to be highly efficient and enantioselective Lewis acid catalysts for carbon- heteroatom double bond reductions (21) and cycloaddition reactions. (18) Oxazaborolidines, also known as Corey – Bakshi – Shibata (CBS) catalysts, were first described by Itsuno et al. in 1983.

(154) The initial study reported that that a stoichiometric amount of a valine derived amino alcohol,

1, in combination with two equivalents of THF•BH3 was able to reduce aryl ketones in good yields with excellent enantioselectivities (≥ 97:3 e.r.). (154)

Figure 1-32 Oxazaborolidine (CBS) catalysts

However, no mechanistic investigations were conducted and the active reducing agent remained ill-defined and the reason for the requirement of two equivalents of borane was left unaddressed. (154) Based on this report, Corey et al. reported that oxazaborolidine 1-14 was produced with concomitant elimination of two equivalents of hydrogen when amino alcohol 1-13 was treated with one equivalent of borane. (155) It was shown that oxazaborolidine 1-14 alone failed to reduce acetophenone at room temperature but was able to promote the reduction in the presence of one equivalent of borane, even with catalytic loadings of Figure 1-33. (155) Thus it was recognized that oxazaborolidine 1-14 was produced in the previous reports of Itsuno and it was highly likely that oxazaborolidine 1-12a was the active reducing agent, explaining the need for two equivalents of borane.

Figure 1-33 Valine derived oxazaborolidine

With the role of 1-14 identified, the below catalytic cycle was proposed, Figure 1-34. First the oxazaborolidine and borane form the Lewis acid-base adduct 1-12. This reduces the electron density at the endocyclic boron (δ = 3.2 ppm vs. δ = 28.3 ppm for uncoordinated oxazaborolidine when R = H), increasing its Lewis acidity. Coordination of the ketone to the same face as the borane follows, yielding 1-17, which can transfer a hydride forming intermediate 1-18. The now reduced ketone is subsequently exchanged with another equivalent of borane, either via a two-step or concerted process, regenerating the catalyst. (21) (155)

Figure 1-34 Catalytic cycle and proposed transition state for CBS reduction

In the studies conducted by Corey et al. they found that proline derived oxazaborolidine 1-

16a afforded considerable improved enantioselectivities than previous valine derived catalysts.

Additionally, slightly increasing the steric bulk of the substituent on the oxazaborolidine boron in,

1-16b further improved the selectivity. (155) The impact of steric effects becomes clear upon closer investigation of the reaction mechanism. Borane can initially coordinate to the catalyst either cis or trans to the bulkier group at the stereogenic carbon-centre. Unfavorable steric interactions in the cis adduct result in the trans conformation being more energetically favorable. In the case of the valine derived oxazaborolidines, the energetic difference between these adducts is not significant enough to lead to exclusive formation of the cis adduct, allowing for formation of the trans adduct contributing to a degeneration in the enantioselectivity of the reduction. However, in the case of the oxazaborolidines of type 1-16, the steric repulsion is considerably higher (ca. 10 kcal/mol) compared to acyclic amino alcohol derived oxazaborolidines due to the strain imposed by the proline ring. Consequently, almost exclusive formation of the cis adduct (the trans-

[3.3.0]pentalane) is observed, accounting for the increased stereoselectivity of the proline-derived catalysts as compared to the valine-derived catalysts. Additionally, following formation of intermediate 1-17, the carbonyl-containing substrate must coordinate cis to the borane to allow for hydride transfer. This coordination again occurs in a fashion to minimize steric repulsion in the interaction between the ketone and the oxazaborolidine (seen above as a more favorable 1,3-diaxial interaction between Me and RS). The increased steric bulk of the B-Methyl substituent in catalyst

1-16b further increases the 1,3-diaxial interaction of the oxazaborolidine catalyst with RL and Rs as compared to catalyst 1-16a (B-H) leading to greater facial selectivity in the transition state for hydride delivery. It should be noted that although presented as such it is not known if the hydride transfer occurs through a chair or boat-like transition state, however both are consistent with overserved stereoselectivity. (21)

Overall, oxazaborolidines have been shown to be highly effective catalysts for enantioselective reductions. Although catalysts 1-12a–c are technically not borenium salts in the strictest sense due to the complexes being overall neutral compounds, the endocyclic boron still comprises a borenium subunit possessing the strongly Lewis acidic/electrophilic B-centre, as compared to the uncomplexed structures e.g. 1-16a and 1-16b. (156) As previously mentioned, this class of catalysts has also be shown to be excellent at promoting enantioselective cycloaddition reactions, which will not be discussed in depth, but has been extensively reviewed. (18) (156)

One of the most interesting developments in the field of borenium catalysis is its application in FLP-type chemistry for the reduction of unsaturated organic moieties. In retrospect, this was a logical application of borenium ions, specifically N-heterocyclic carbene (NHC)- stabilized boreniums. Firstly, the high Lewis acidity of borenium ions (156) and the correspondingly high Lewis acidities required for hydrogen activation made them excellent targets for investigation as catalysts. (106) Secondly, it had previously been shown that NHCs were effective ligands for the stabilization of borenium ion motifs (157) and that their corresponding

NHC – borane adducts were exceptional hydride donors, capable of reducing a variety of unsaturated moieties. (158) (159) (157) For these reasons, NHC-stabilized borenium cations seemed like an excellent target to investigate as FLP-type hydrogenation catalysts. (161)

Stephan et al. were able to show that borenium ions could be effective at activating dihydrogenation directly. In their initial report, they were able to successfully synthesize borenium

1-20, by hydride abstraction from NHC-borane 1-19. Borenium 1-20 was shown to be able to split

t hydrogen in the presence of Bu3P and generate NHC-borane 1-19 along with the corresponding

t + - phosphonium salt [ Bu3PH B(C6F5)4 ]. The NHC-borane and phosphine salt mixture was able to

t t stoichiometrically reduce the imine PhCH=N Bu, and regenerate the borenium ion 1-20/ Bu3P pair, providing excellent evidence that 1-20 would be an active hydrogenation catalyst. Indeed, borenium 1-20 was able to reduce PhCH=NtBu at 102 atmospheres of hydrogen gas in good yield, as well as 8-methylquinoline in moderate yield. Based on these results the following catalytic cycle was proposed, Figure 1-35.

Figure 1-35 Proposed catalytic cycle for NHC borenium-catalyzed hydrogenation

Borenium 1-20, in concert with an imine, heterolytically splits dihydrogen generating NHC-borane

1-19 and a protonated imine. The imine is rendered more electrophilic by protonation allowing for hydride attack by 1-19 at the imine carbon, subsequently regenerating borenium 1-20 and formation of the amine product. (161)

In a follow-up study, Stephan et al. were able to improve upon their previous catalyst and expand the substrate scope of borenium catalyzed reductions. In this report, they showed that a decrease of the steric bulk of the NHC wingtip groups and introducing electron-withdrawing substituents in the NHC-back led to an increase in catalyst activity. (162) This suggested that bulkier NHCs either interfere with the efficiency of dihydrogen activation or hydride delivery to the activated substrate. Given that hydride delivery is generally not rate limiting in FLP systems,

(59) it seems most likely the reduced steric bulk allows for more facile formation of the encounter complex resulting in more efficient hydrogen activation accounting and the increase in catalyst activity. Furthermore, the weaker σ-donating/more electronically poor NHCs donated less electron density to the borenium centre leading to an increase of the Lewis acidity of the catalyst.

Consequently, the borenium ion derived from 20 could achieve a turn over frequency (TOF) of 940 h-1, comprising the most active FLP catalyst reported up until that point. (162) In terms of substrate scope, it was found that 20 was able to catalyze the reduction of a variety of aromatic aldimines, ketamines, as well as 8-methyl-quinoline, Figure 1-36. Both electron-rich and electron-poor aromatic imines were well tolerated as well as ortho-bulk on the N-aryl substituent. Somewhat surprisingly, sterically unencumbered esters were also well tolerated and were not subjected to reduction, in contrast to previous reports of FLP catalysts where sterically unencumbered esters inhibited reduction. (163) Unfortunately substrates that were less sterically encumbered at the nitrogen centre were less well tolerated resulting in only partial or no reduction. (162)

Figure 1-36 Substrate scope of borenium 1-20 catalyzed reductions

1.6 Research Objectives

From the literature reviewed above it is hoped that it is clear the field of Lewis acid- base/main-group catalysis is synthetically valuable, as well as undergoing a new resurgence thanks to the work on BCF catalyzed hydrosilylation in the 90s by Piers et al. (139) (71) and the more recent developments in FLP chemistry. (59) (164) (100) It is the purpose of this thesis to further investigate these fields, applying previous research done in the Crudden group. Investigations into mesoionic carbene (MIC) boranes in our lab showed that these compounds were excellent hydride donors and led us to speculate that MICs would be excellent ligands for the stabilization of borenium ions, which we hoped to use as Lewis acid catalysts. (165) We plan to develop a library of MIC-boranes/borenium ions and investigate their ability to activate as dihydrogen as well as other molecules such as silanes, Figure 1-37.

Figure 1-37 Proposed meso-ionic carbene borenium catalytic manifold

Furthermore, if these compounds prove to be catalytically competent, we plan to investigate ways that asymmetry may be implemented into the catalytic in the hopes of developing an enantioselective catalyst. One way we propose to accomplish this is to use a chiral borane such as the [3.3.2]9-borobicyclodecanes (BBDs), Figure 1-38, an exceptionally versatile class of borylation regents. (166)

Figure 1-38 The chiral borane, 10-Substituted-[3.3.2]9-borobicyclodecane (BBD)

In addition to the borenium ion catalysis previously discussed, we are also interested in the

use of boron compounds as nucleophilic catalysts, specifically as enantioselective hydrosilylation

catalysts. Crabtree et al. have shown that borohydrides can be used catalytically to hydrosilylation

a variety of compounds. We plan to explore this reaction using the same chiral boranes that we are

going to investigate as chiral borenium catalysts, Figure 1-39. (167)

Figure 1-39 Chiral borohydride catalyzed hydrosilylation

1.7 Thesis Objectives

The Objectives of this thesis are three-fold:

1. Develop and investigate the use of MIC-borenium ions as FLP-type hydrogenation catalysts

2. Develop enantioselective variants of the MIC-borenium ion hydrogenation catalyst using BBDs

3. Investigate the use of BBDs as an enantioselective nucleophilic hydrosilylation catalysts.

1.8 Chapter 1 References

1. de Vries, J. G., Elsevier, C. J., Eds. The Handbook of Homogeneous Hydrogenation; Wiley- VCH Verlag GmbH: Weinheim Germany, 2008.

2. Arnold, J. Dalton Discussion 11: The Renaissance of Main Group Chemistry. Dalton Transactions 2008, 4334. 3. Jones, C.; Koutsantonis, G. Modern Main Group Chemistry: From Renaissance to Revolution. Australian Journal of Chemistry 2013, 66, 1115. 4. Koutsantonis, G. A.; Jones, C. Modern Main Group Chemistry: From Renaissance to Revolution. Australian Journal of Chemistry 2013, 66, 1115. 5. Lewis, G. N. Valence and the Structure of Atoms and Molecules; Chemical Catalog: New York, 1923. 6. Jensen, W. B. The Lewis Acid-Base Definitions: A Status Report. Chemistry Reviews 1978, 1, 78. 7. Denmark, S. E. Lewis Base Catalysis in Organic Synthesis. Angewandte Chemie International Edition 2008, 47, 1560. 8. Hewitt, F.; Holliday, A. K. The Reaction of Diborane with the Alkyl Derivaties of Some Group VB Elements. Journal of the Chemical Society 1953, 530. 9. Gutmann, V. Empirical Approach to Molecular Interactions. Coordination Chemistry Reviews 1975, 15, 207. 10. Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in Organic Synthesis; CRC Press: Boca Raton, FL, 1999.

11. Mukaiyama, T.; Narasaka, K.; Banno, K. New Aldol Type Reaction. Chemistry Letters 1973, 2, 1011. 12. Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. The Efficient Catalytic Asymmetric Aldol-type Reaction. Chemistry Letters 1990, 19, 1455. 13. Evans, D. A.; Macmillan, D. W. C.; Campos, K. R. C2-Symmetric Tin(II) Complexes as Chiral Lewis Acids. Catalytic Enantioselective Anti Aldol Additions of Enolsilanes to Glyoxylate and Pyruvate Esters. Journal of the American Chemical Society 1997, 119, 10859.

14. Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. Highly anti-Selective Asymmetric Aldol Reactions Using Chiral Zirconium Catalysts. Improvement of Activities, Structure of the Novel Zirconium Complexes, and Effect of a Small Amount of Water for the Preparation of the Catalysts. Journal of the American Chemical Society 2002, 124, 3292. 15. Carreira, E. M.; Singer, R. A.; Lee, W. Catalytic, Enantioselective Aldol Additions with Methyl and Ethyl Acetate O-Silyl Enolates: A Chiral Tridentate Chelate as a Ligand for Titanium(IV). Journal of the American Chemical Society 1994, 116, 8837. 16. Carreira, E. M.; Lee, W.; Singer, R. A. Catalytic, Enantioselective Acetone Aldol Additions with 2-Methoxypropene. Journal of the American Chemical Society 1995, 117, 3649. 17. Corey, E. J. Catalytic Enantioselective Diels–Alder Reactions: Methods, Mechanistic Fundamentals, Pathways, and Applications. Angewandte Chemie International Edition 2002, 41, 1650. 18. Corey, E. J. Enantioselective Catalysis Based on Cationic. Angewandte Chemie International Edition 2009, 48, 2100. 19. Reddy, K. M.; Bhimireddy, E.; Thirupathi, B.; Breitler, S.; Yu., S.; Corey, E. J. Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions. Journal of the American Chemical Society 2016, 138, 2443. 20. Lee, T. W.; Corey, E. J. Enantioselective Total Synthesis of Eunicenone A. Journal of the American Chemical Society 2001, 123, 1872. 21. Corey, E. J.; Helal, C. J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angewante Chemie International Edition 1998, 37, 1986. 22. Katsuki, T.; Sharpless, K. B. The First Practical Method for Asymmetric Epoxidation. Journal of the American Chemical Society 1980, 102, 5974. 23. Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Whiley-VCH: New York, 2000; p 231. 24. Hoye, T. R.; Ye, Z. Highly Efficient Synthesis of the Potent Antitumor Annonaceous Acetogenin (+)-Parviflorin. Journal of the American Chemical Society 1996, 118, 1801.

25. Paterson, I.; De Savi, C.; Tudge, M. Total Synthesis of the Microtubule-Stabilizing Agent (- )-Laulimalide. Organic Letters 2001, 3, 3149. 26. Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi, M.; Komiyama, K.; Omura, S.; Smith, A. B. III. Total Synthesis of (+)-Madindoline A and (-)-Madindoline B, Potent, Selective Inhibitors of Interleukin 6. Determination of the Relative and Absolute Configurations. Journal of the American Chemical Society 2000, 122, 2122. 27. Gabarda, A. E.; Du, W.; Isamo, T.; Tangirala, R. S.; Curran, D. P. Asymmetric Total Synthesis of (20R)-Homocamptothecin, Substituted Homocamptothecins and Homosilatecans. Tetrahedron 2002, 58, 6329. 28. Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: San Diego, 2005. 29. Kirichenko, A. I.; Litvinenko, L. M. Basicity and Stereospecificity in Nucleophilic Catalysis by Tertiary Amines. Doklady Akademii Nauk SSSR 1967, 176, 197. 30. Steglich, W.; Höfle, G. N,N-Dimethyl-.l-pyridinamine, a Very Effective Acylation Catalyst. Angewandte Chemie International Edition 1969, 8, 981. 31. Einhorn, A.; Hollandt, F. Ueber die Acylirung der Alkohole und Phenole in Pyridinlösung. Justus Liebigs Annalen der Chemie 1898, 301, 95.

32. Xu, S.; Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. The DMAP-Catalyzed Acetylation of Alcohols—A Mechanistic Study (DMAP=4-(Dimethylamino)pyridine). Chemistry - A European Journal 2005, 11, 4751. 33. Spivey, A. C.; Arseniyadis, S. Nucleophilic Catalysis by 4-(Dialkylamino)pyridines Revisited—The Search for Optimal Reactivity and Selectivity. Angewandte Chemie International Edition 2004, 43, 5436. 34. Ruble, J. C.; Latham, H. A.; Fu, G. C. Effective Kinetic Resolution of Secondary Alcohols

with a Planar−Chiral Analogue of 4-(Dimethylamino)pyridine. Use of the Fe(C5Ph5) Group in Asymmetric Catalysis. Journal of the American Chemical Society 1997, 119, 1492.

35. Ruble, J. C.; Tweddel, J.; Fu, G. C. Kinetic Resolution of Arylalkylcarbinols Catalyzed by a Planar-Chiral Derivative of DMAP: A New Benchmark for Nonenzymatic Acylation. Journal of Organic Chemistry 1998, 63, 2794.

36. Le, Y.; Fu, G. C. A New Benchmark for the non-Enzymatic Enantioselective Acylation of Amines: use of a Planar-Chiral Derivative of 4-Pyrrolidinopyridine as the Acylating Agent. Chemical Communications 2000, 119. 37. Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Kinetic Resolution of Amines by a Nonenzymatic Acylation Catalyst. Angewandte Chemie International Edition 2001, 40, 234. 38. Lee, S. Y.; Murphy, J. M.; Ukai, A.; Fu, G. C. Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via Enantioselective Acylation: Synthetic and Mechanistic Studies. Journal of the American Chemical Society 2012, 134, 15149.

39. Orito, Y.; Nakajima, M. Lewis Base Catalyzed Asymmetric Reactions Involving Hypervalent Silicate. Synthesis 2006, 9, 1391. 40. Rendler, S.; Oestreich, M. Hypervalent Silicon as a Reactive Site in Selective Bond-Forming Processes. Synthesis 2005, 11, 1727. 41. Jensen, W. B. The Lewis Acid-Base Concepts; Wiley-Interscience: New York, 1980. 42. Kira, M.; Sato, K.; Sakurai, H.; Hada, M.; Izawa, M.; Ushio, J. Ab Initio MO Study of the Reaction of Pentacoordinate Allylsilicates with Aldehydes. Chemistry Letters 1991, 20, 387. 43. Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Catalytic Enantioselective Allylation of Carbonyl Compounds. Chemical Reviews 2011, 111, 7774.

44. Gawronski, J.; Wascinska, N.; Gajewy, J. Recent Progress in Lewis Base Activation and Control of Stereoselectivity in the Additions of Trimethylsilyl Nucleophiles. Chemical Reviews 2008, 108, 5227. 45. Hosomi, A.; Shirahata, A.; Sakurai, H. Chemoselective Allylation of Carbonyl Compounds with Allylsilanes Promoted by Terta-n-Butylammonium Fluroide. A New Synthesis of Homoallyl Alcohols. Tetrahedron Letters 1978, 33, 3043.

46. Wang, Z.; Kisanga, P.; Verkade, J. G. P(i-PrNCH2CH2)3N: An Effective Lewis Base Promoter for the Allylation of Aromatic Aldehydes with Allyltrimethylsilane. Journal of Organic Chemistry 1999, 64, 6459.

47. Biddle, M. M.; Reich, H. J. Studies on the Reactive Species in Fluoride-Mediated. Journal of Organic Chemistry 2006, 71, 4031. 48. Noyori, R.; Nishida, I.; Sakata, J. Tris(dialkylamino)sulfonium Enolates. Synthesis, Structure, And Reactions. Journal American Chemical Society 1983, 105, 1598.

49. Mukaiyama, T.; Fujisawa, H.; Nakagawa, T. Lewis Base Catalyzed Aldol Reaction of Trimethylsilyl Enolates with Aldehydes. Helvetica Chimica Acta 2002, 85, 4518. 50. Matsukawa, S.; Okano, N.; Imamoto, T. Phosphine Catalyzed Aldol Reaction Between Ketene Silyl Acetals. Tetrahedron Letters 2000, 41, 103. 51. Kira, M.; Kobayashi, M.; Sakurai, H. Regiospecific and Highly Stereoselective Allylation of Aldehydes with Allyltrifluorosilane Activated by Fluoride Ions. Tetrahedron Letters 1987, 28, 4081. 52. Kira, M.; Hino, T.; Sakurai, H. Stereohomogeneous Synthesis of (E)- and (Z)- Crotyltrifluorosilanes and Highly Stereoselectrive Allylation of Aldehydes. Tetrahedron Letters 1989, 30, 1099. 53. Kobayashi, S.; Nishio, K. Facile and Highly Stereoselective Allylation of Aldehydes Using Allyltrichlorosilanes in DMF. Tetrahedron Letters 1993, 34, 3453. 54. Kobayashi, S.; Nishio, K. Facile and Highly Stereoselective Synthesis of Homoallylic Alcohols Using Organosilicon Intermediates. Journal of Organic Chemistry 1994, 59, 6620. 55. Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. Asymmetric Allylation of Aldehydes with Chiral Lewis Bases. Journal of Organic Chemistry 1994, 59, 6161. 56. Denmark, S. E.; Fu, J. On the Mechanism of Catalytic, Enantioselective Allylation of Aldehydes with Chlorosilanes and Chiral Lewis Bases. Journal of the American Chemical Society 2000, 122, 12021. 57. Denmark, S. E.; Fu, J.; Coe, D. M.; Su, X.; Pratt, N. E.; Griedel, B. D. Chiral Phosphoramide- Catalyzed Enantioselective Addition of Allylic Trichlorosilanes to Aldehydes. Preparative and Mechanistic Studies with Monodentate Phosphorus-Based Amides. Journal of Organic Chemistry 2006, 71, 1513. 58. Denmark, S. E.; Fu, J. Catalytic, Enantioselective Addition of Substituted Allylic Trichlorosilanes Using a Rationally-Designed 2,2‘-Bispyrrolidine-Based Bisphosphoramide. Journal of the American Chemical Society 2001, 123, 9488.

59. Erker, G., Stephan, D. W., Eds. Frustrated Lewis Pairs I - Uncovering and Understanding; Springer: Berlin, German, 2013; pp 196-198. 60. Rokob, T. A.; Pápai, I. Hydrogen Activation by Frustrated Lewis Pairs: Insights from Computational Studies. In Frustrated Lewis Pairs; Erker, G., Stephan, D. W., Eds.; Springer Berlin Heidelberg: New York, 2013; Vol. 1, 2 vols., p 168.

61. Covert, L. W.; Adkins, H. Nickel by the Raney Process as a Catalyst of Hydrogenation. Journal of the American Chemicals Soceity 1392, 54, 4116. 62. Adams, R.; Voorhees, V. The use of the Oxides of Platinum for the Catalytic Reduction of Organic Compounds. I. Journal of the American Chemical Society 1922, 44, 1397. 63. Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. The Preparation and Properties of Tris(triphenylphosphine)halogenorhodium(I) and Some Reactions Thereof Including Catalytic Homogeneous Hydrogenation of Olefins and Acetylenes and their Derivatives. Journal of the Chemical Society A; Inorganic, Physical, Theoretical 1966, 1711.

64. Crabtree, R. H.; Felkin, H.; Morris, G. E. Cationic Iridium Diolefin Complexes as Alkene Hydrogenation Catalysts and the Isolation of Some Related Hydrido Complexes. Journal of Organometallic Chemistry 1977, 141, 205. 65. Clarke, M. L.; Roff, G. J. Homogeneous Hydrogenation of Aldehydes, Ketones, Imines and Carboxylic Acid Derivaties: Chemoselectivity and Catalytic Activity. In Handbook of Homogeneous Hydrogenation; de Vries, J., Elsevier, C. J., Eds.; Wiley-VCH Verlag GmbH: Weinheim Germany, 2007; Chapter 15, Vol. 1, 3 vols., p 413. 66. Walling, C.; Bollyky, L. Base Catalyzed Homogeneous Hydrogenation. Journal of the American Chemical Society 1961, 83, 2968.

67. DeWitt, E. J.; Ramp, F. L.; Trapasso, L. E. Homogeneous Hydrogenation Catalyzed by Boranes. Journal of the American Chemical Society 1961, 83, 4672. 68. Siskin, M.; Porcello, J. Strong Acid Chemistry. II. Catalytic Hydrogenation of Aromatics in Hydrogen Fluoride-Tantalum Pentafluoride and Related Stong Acid Systems. Journal of the American Chemical Society 1974, 96, 3641. 69. Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Reversible, Metal-Free Hydrogen Activation. Science 2006, 314, 1124. 70. Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Metal-Free Catalytic Hydrogenation. Angewandte Chemie International Edition 2007, 46, 8050.

71. Parks, J. D.; Blackwell, J. M.; Piers, W. E. Studies on the Mechanism of B(C6F5)3-Catalyzed Hydrosilation of Carbonyl Functions. Journal of Organic Chemistry 2000, 65, 3090. 72. Spies, P.; Erker, G.; Bergander, K.; Fröhlich, R.; Grimme, S.; Stephan, D. W. Rapid Intramolecular Heterolytic Dihydrogen Activation by a Four-Membered Heterocyclic Phosphane–Borane Adduct. Chemical Communications 2007, 5072.

73. Schwendemann, S.; Fröhlich, R.; Kehr, G.; Erker, G. Intramolecular Frustrated N/B Lewis Pairs by Enamine Hydroboration. Chemical Science 2011, 2, 1842. 74. Sumerin, V.; Schulz, F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskelä, M.; Repo, T.; Pyykkö, P.; Rieger, B. Molecular Tweezers for Hydrogen: Synthesis, Characterization, and Reactivity. Journal of the American Chemical Society 2008, 130, 14117. 75. Wang, H.; Fröhlich, R.; Kehr, G.; Erker, G. Heterolytic Dihydrogen Activation with the 1,8-

Bis(diphenylphosphino)-Naphthalene/B(C6F5)3 Pair and its Application for Metal-Free Catalytic Hydrogenation of Silyl Enol Ethers. Chemical Communications 2008, 5966.

76. Greb, L.; Oña-Burgos, P.; Schirmer, B.; Grimme, S.; Stephan, D. W.; Paradies, J. Metal-free

Catalytic Olefin Hydrogenation: Low-Temperature H2 Activation by Frustrated Lewis Pairs. Angewandte Chemie International Edition 2012, 51, 10164. 77. Welch, G. C.; Stephan, D. W. Facile Heterolytic Cleavage of Dihydrogen by Phosphines and Boranes. Journal of the American Chemical Society 2007, 129, 1880. 78. Reddy, J. S.; Xu, B.; Mahdi, T.; Fröhlich, R.; Kehrt, G.; Stephan, D. W. Alkenylborane- Derived Frustrated Lewis Pairs: Metal-Free Catalytic Hydrogenation Reactions of Electron- Deficient Alkenes. Organometallics 2012, 31, 5638. 79. Appelt, C.; Westenberg, H.; Bertini, F.; Ehlers, A. W.; Slootweg, J. C.; Lammertsma, K.; Uhl, W. Geminal Phosphorus/Aluminum-Based Frustrated Lewis Pairs: C-H versus C≡C

Activation and CO2 Fixation. Angewandte Chemie International Edition 2011, 50, 3925. 80. Schafer, A.; Reissmann, M.; Schafer, A.; Saak, W.; Haase, D.; Muller, T. A New Synthesis of Triarylsilylium Ions and Their Application in Dihydrogen Activation. Angewandte Chemie Internation Edition 2011, 50, 12636. 81. Reissmann, M.; Schafer, A.; Jung, S.; Muller, T. Silylium Ion/Phosphane Lewis Pairs. Organometallics 2013, 32, 6736.

+ 82. Clark, E. R.; Ingleson, M. J. [(acridine)BCl2] : A Borenium Cation That Is a Strong Boron- and Carbon-Based Lewis Acid. Organometallics 2013, 32, 6712.

83. Clark, E. R.; Ingleson, M. J. N-Methylacridinium Salts: Carbon Lewis Acids in Frustrated Lewis Pairs for σ-Bond Activation and Catalytic Reductions. Angewandte Chemie International Edition 2014, 53, 11306. 84. Bayne, J. M.; Stephane, D. W. Phosphorus Lewis Acids: Emerging Reactivity and Applications in Catalysis. Chemical Society Reviews 2016, 45, 765.

85. Frey, G. D.; Lavallo, V.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Facile Splitting of Hydrogen and Ammonia by Nucleophilic Activation at a Single Carbon Center. Science 2007, 316, 439. 86. Chase, P. A.; Stephan, D. W. Hydrogen and Amine Activation by a Frustrated Lewis Pair of

a Bulky N-Heterocyclic Carbene and B(C6F5)3. Angewandte Chemie International Edition 2008, 47, 7433.

87. Chase, P. A.; Jurca, T.; Stephan, D. W. Lewis Acid-Catalyzed Hydrogenation: B(C6F5)3-

Mediated Reduction of Imines and Nitriles with H2. Chemical Communications 2008, 1701. 88. Chen, D.; Klankermayer, J. Metal-Free Catalytic Hydrogenation of Imines with Tris(perfluorophenyl)borane. Chemical Communications 2008, 2130. 89. Geier, S. J.; Chase, P. A.; Stephan, D. W. Metal-Free Reductions of N-Heterocycles via Lewis Acid Catalyzed Hydrogenation. Chemical Communications 2010, 46, 4884. 90. Chernichenko, K.; Madarasz, A.; Papai, I.; Nieger, M.; Leskela, M.; Repo, T. A Frustrated- Lewis-Pair Approach to Catalytic Reduction of Alkynes to cis-Alkenes. Nature Chemistry 2013, 5, 718. 91. Greb, L.; Damiliuc, C.; Bergander, K.; Paradies, J. Functional-Group Tolerance in Frustrated Lewis Pairs: Hydrogenation of Nitroolefins and Acrylates. Angewandte Chemie International Edition 2013, 52, 5876. 92. Erős, G.; Nagy, K.; Mehdi, H.; Pápai, I.; Nagy, P.; Király, P.; Tárkányi, G.; Soós, T. Catalytic Hydrogenation with Frustrated Lewis Pairs: Selectivity Achieved by Size-Exclusion Design of Lewis Acids. Chemistry a European Journal 2012, 18, 574. 93. Chapman, A. M.; Haddow, M. F.; Wass, D. F. Frustrated Lewis Pairs beyond the Main Group: Synthesis, Reactivity, and Small Molecule Activation with Cationic Zirconocene– Phosphinoaryloxide Complexes. Journal of the American Chemical Society 2011, 133, 18463. 94. Momming, C. M.; Otten, E.; Kehr, G.; Frohlich, R.; Grimme, S.; Stephan, D. W.; Erker, G. Reversible Metal-Free Carbon Dioxide Binding by Frustrated Lewis Pairs. Angewandte Chemie International Edition 2009, 48, 6643. 95. Otten, E.; Neu, R. C.; Stephan, D. W. Complexation of Nitrous Oxide by Frustrated Lewis Pairs. Journal of the American Chemical Society 2009, 131, 9918.

96. Cardenas, A. J. P.; Culotta, B. J.; Warren, T. H.; Grimme, S.; Stute, A.; Frohlich, R.; Kehr, G.; Erker, G. Capture of NO by a Frustrated Lewis Pair: A New Type of Persistent N-Oxyl Radical. Angewandte Chemie International Edition 2011, 50, 7567. 97. Sajid, M.; Klose, A.; Birkmann, B.; Liang, L.; Schirmer, B.; Wiegand, T.; Eckert, H.; Lough, A. J.; Frohlich, R.; Daniliuc, C. G.; Grimme, S.; Stephan, D. W.; Kehr, G.; Erker, G.

Reactions of phosphorus/boron frustrated Lewis pairs with SO2. Chemical Science 2013, 4, 213. 98. Longobardi, L. E.; Wolter, V.; Stephan, D. W. Frustrated Lewis Pair Activation of an Sulfur Monoxide. Angewandte Chemie International Edition 2015, 54, 809. 99. Chen, D.; Klankermayer, J. Frustrated Lewis Pairs: From Dihydrogen Activation to Asymmetric Catalysis. In Frustrated Lewis Pairs II, 1st ed.; Erker, G., Stephan, D. W., Eds.; Springer-Verlag: Berlin, Heidelberg Germany, 2013; p 1. 100. Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.; Ullrich, M. Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs. Inorganic Chemistry 2011, 50, 12338. 101. Sumerin, V.; Cherinchenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Highly Active Metal-Free Catalysts for Hydrogenation of Unsaturated Nitrogen-Containing Compounds. Advanced Synthesis & Catalysis 2011, 353, 2093. 102. Chen, D.; Wang, Y.; Klankermayer, J. Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs. Angewandte Chemie International Edition 2010, 49, 9475. 103. Liu, Y.; Du, H. Chiral Dienes as "Ligands" for Borane-Catalyzed Metal-Free Asymmetric Hydrogenation of Imines. Journal of the American Chemical Society 2013, 135, 6810. 104. Lindqvist, M.; Borre, K.; Axenov, K.; Kotai, B.; Nieger, M.; Leskela, M.; Papai, I.; Repo, T. Chiral Molecular Tweezers: Synthesis and Reactivity in Asymmetric Hydrogenation. Journal of the American Chemical Society 2015, 137, 4038.

105. Rokob, T. A.; Hamza, A.; Stirling, A.; Soós, T.; Pápai, I. Turning Frustration into Bond Activation: A Theoretical Mechanistic Study on Heterolytic Hydrogen Splitting by Frustrated Lewis Pairs. Angewandte Chemie International Addition 2008, 47, 2435. 106. Rokob, T. A.; Hamza, A.; Pápai, I. Rationalizing the Reactivity of Frustrated Lewis Pairs:

Thermodynamics of H2 Activation and the Role of Acid-Base Properties. Journal of the American Chemical Society 2009, 131, 10701.

107. Rokob, T. A.; Bakó, I.; Stirling, A.; Hamza, A.; Pápai, I. Reactivity Models of Hydrogen Activation by Frustrated Lewis Pairs: Synergistic Electron Transfers or Polarization by Electric Field? Journal of the American Chemical Society 2013, 135, 4425. 108. Grimme, S.; Kruse, H.; Goerigk, L.; Erker, G. The Mechanism of Dihydrogen Activation by Frustrated Lewis Pairs Revisited. Angewandte Chemie International Edition 2010, 49, 1402. 109. Hartwig, J. F. Organotransition Metal Chemistry From Bonding to Catalysis, 1st ed.; University Science Books: Sausalito, CA, 2010. 110. Lu, Z.; Cheng, Z.; Chen, Z.; Weng, L.; Li, Z. H.; Wang, H. Heterolytic Cleavage of Dihydrogen by “Frustrated Lewis Pairs” Comprising Bis(2,4,6- tris(trifluoromethyl)phenyl)borane and Amines: Stepwise versus Concerted Mechanism. Angewandte Chemie International Edition 2011, 50, 12227.

- 111. Gao, S.; Mo, Y. The B - H ··· H - P Dihydrogen Bonding in Ion Pair Complexes [(CF3)3BH

+ ][HPH3-n(Me)n ](n = 0-3) and Its Implication in H2 Elimination and Activation Reactions. Journal of Physical Chemistry A 2009, 113, 8108. 112. Fan, C.; Mercier, L. G.; Piers, W. E.; Tuononen, H. M.; Parvez, M. Dihydrogen Activation by Antiaromatic Pentaarylboroles. Journal of the American Chemical Society 2010, 132, 9604.

113. Ojima, I. The Chemistry of Organic Silicon Compounds, Vol.; Wiley: Chichester, 1989. 114. Marciniec, B.; Gulinsky, J.; Urbaniak, W.; Kornetka, Z. W. Comprehensive Handbook on Hydrosilylation; Pergamon: Oxford, 1992. 115. Pukhnarevich, V. B.; Lukevics, E.; Kopylova, L. T.; Voronkov, M. G. Perspectives of Hydrosilylation; Institute of Organic Synthesis: Riga, 1992. 116. Brook, M. A. Silicon in Organic, Organometallic, and Polymer Chemistry; Wiley: New York, 2000. 117. Marciniec, B.; Maciejewski, H.; Pietraszuk, C.; Pawluc, P. Hydrosilylation: A Comprehensive Review on Recent Adances; Spring: New York, 2009.

118. Speier, J. L.; Webster, J. A.; Barnes, G. H. The Addition of Silicon Hydrides to Olefinic Double Bonds. Part II. The Use of Group VIII Metal Catalysts. Journal of the American Chemical Society 1957, 79, 974. 119. Marciniec, B. Catalysis by Transition Metal Complexes of Alkene Silylation – Recent Progress and Mechanistic Implications. Coordination Chemistry Review 2005, 249, 2374.

120. Ojima, I.; Clos, N.; Donovan, R. J.; Ingallina, P. Hydrosilylation of 1-Hexyne Catalyzed by Rhodium and Cobalt-Rhodium Mixed-Metal Complexes. Mechanism of Apparent trans Addition. Organometallics 1990, 9, 3127. 121. Jun, C.; Crabtree, R. H. Dehydrogenative Ailation, Isomerization and the Control of syn- vs. anti-Addition in the Hydrosilation of Alkynes. Journal of Organometallic Chemistry 1993, 447, 177. 122. Uozumi, Y.; Hayashi, H. Catalytic Asymmetric Synthesis of Optically Active 2-Alkanols via Hydrosilylation of 1-Alkenes with a Chiral Monophosphine-Palladium Catalyst. Journal of the American Chemical Society 1991, 113, 9887. 123. Uozumi, Y.; Kitayama, K.; Hayashi, T.; Yanagi, K.; Fukuyo, E. Asymmetric Hydrosilylation of 1-Alkenes Catalyzed by Palladium–MOP. Bulletin of the Chemical Society of Japan 1995, 68, 713. 124. Uozumi, Y.; Hayashi, T. Catalytic Asymmetric Synthesis of Optically Active Alcohols via Hydrosilylation of Olefins with a Chiral Monophosphine-Palladium Catalyst. Pure and Applied Chemistry 1992, 64, 1911. 125. Uozumi, Y.; Hayashi, T. Asymmetric Hydrosilylation of Dihydrofurans by use of Palladium- MOP Catalyst. Tetrahedron Letters 1993, 34, 2335.

126. Uozumi, Y.; Sang-Yong, L.; Hayashi, T. Asymmetric Functionalization of Bicycloalkenes by Catalytic Enantioposition-Selective Hydrosilylation. Tetrahedron Letters 1992, 33, 7185. 127. Ojima, I.; Nihonyanagi, M.; Nagai, Y. Rhodium Complex Catalysed Hydrosilylation of Carbonyl Compounds. Journal of the Chemical Society, Chemical Communications 1972, 938. 128. Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Highly Enantioselective Hydrosilylation

of Ketones with Chiral and C2-Symmetrical Bis(oxazolinyl)pyridine-Rhodium Catalysts. Organometallics 1991, 10, 500. 129. Goldberg, Y.; Alper, H. Asymmetric Hydrosilylation of Prochiral Ketones Catalyzed by Rh(I) Complexes and (−)-Sparteine. Tetrahedron: Asymmetry 1992, 3, 1055. 130. Sawamura, M.; Kuwano, R.; Ito, Y. trans-Chelating Chiral Diphosphane Ligands Bearing Flexible P-Alkyl Substituents (AlkylTRAPs) and their Application to the Rhodium- Catalyzed Asymmetric Hydrosilylation of Simple Ketones. Angewante Chemie Internation Edition 1994, 33, 111.

131. Mimoun, H.; de Saint Laumer, J. Y.; Giannini, L.; Scopelliti, R.; Floriani, C. Enantioselective Reduction of Ketones by Polymethylhydrosiloxane in the Presence of Chiral Zinc Catalysts. Journal of the American Chemical Society 1999, 121, 6158. 132. Mastranzo, V. M.; Quintero, L.; de Parrodi, C. A.; Juaristi, E.; Walsh, P. J. Use of Diamines Containing the α-Phenylethyl Group as Chiral Ligands in the Asymmetric Hydrosilylation of Prochiral Ketones. Tetrahedron 2004, 60, 1781. 133. Bette, V.; Mortreux, A.; Ferioli, F.; Martelli, G.; Savoia, D.; Carpentier, J.-F. New Chiral 1,2-Diamines and Their Use in Zinc-Catalyzed Asymmetric Hydrosilylation of Acetophenone. European Journal of Organic Chemistry 2004, 3040. 134. Hojo, M.; Fujii, A.; Murakami, C.; Aihara, H.; Hosomi, A. Divergent Stereoselectivity in the Reduction of α,β-Epoxy Ketones using Hydridosilicates. Tetrahedron Letters 1995, 36, 571. 135. Hojo, M.; Murakami, C.; Fujii, A.; Hosomi, A. New Reactivity of Methoxyhydridosilane in the Catalytic Activation System. Tetrahedron Letters 1999, 40, 911. 136. Deneux, M.; Akhrem, I. C.; Avetissian, D. V.; Myssoff, E. I.; Vol'pin, M. E. Bulletin of the Chemical Society of France 1973, 2638. 137. Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Reactivity of Penta- and Hexacoordinate Silicon Compounds and Their Role as Reaction Intermediates. Chemical Reviews 1993, 93, 1371. 138. Hiyama, T.; Fujita, M. Fluoride Ion-Catalyzed Reduction of Aldehydes and Ketones with Hydrosilanes. Synthetic and Mechanistic Aspects and an Application to the Threo-Directed Reduction of Alpha-Substituted Alkanones. The Journal of Organic Chemistry 1988, 53, 5405. 139. Parks, D. J.; Piers, W. E. Tris(pentafluorophenyl)boron-Catalyzed Hydrosilation of Aromatic Aldehydes, Ketones, and Esters. Journal of the American Chemical Society 1996, 118, 9440.

140. Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E. B(C6F5)3-Catalyzed Hydrosilation of Imines via Silyliminium Intermediates. Organic Letters 2000, 2, 3921.

141. Gandhamsetty, N.; Joung, S.; Park, S.-W.; Park, S.; Chang, S. Boron-Catalyzed Silylative Reduction of Quinolines: Selective sp3 C−Si Bond Formation. Journal of the American Chemical Society 2014, 136, 16780.

142. Rendler, S.; Oestreich, M. Conclusive Evidence for an SN2-Si Mechanism in the B(C6F5)3- Catalyzed Hydrosilylation of Carbonyl Compounds: Implications for the Related Hydrogenation. Angewandte Chemie International Edition 2008, 47, 5997. 143. Houghton, A. Y.; Hurmalainen, J.; Mansikkamaki, A.; Piers, W. E.; Tuononen, H. M. Direct Observation of a Borane–Silane Complex Involved in Frustrated Lewis-Pair-Mediated Hydrosilylations. Nature Chemistry 2014, 6, 983. 144. Pini, D.; Luliano, A.; Salvadori, P. Optically Active Lithium 1,2-Diphenyl-1,2- Ethanediolate: an Efficient Chiral Auxiliary in the Enantioselective Hydrosilylation of Ketones. Tetrahedron: Asymmetry 1992, 3, 693. 145. Schiffers, R.; Kagan, H. B. Asymmetric Catalytic Reduction of Ketones with Hypervalent Trialkoxysilanes. Synlett 1997, 10, 1175. 146. Malkov, A. V.; Stewart LIddon, A. J. P.; Ramirez-Lopez, P.; Bendova, L.; Haigh, D.; Kočovský, P. Remote Chiral Induction in the Organocatalytic Hydrosilylation of Aromatic Ketones and Ketimines. Angewandte Chemie International Edition 2006, 45, 1432. 147. Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Evolution of Chiral Lewis Basic N-Formamide as Highly Effective Organocatalyst for Asymmetric Reduction of Both Ketones and Ketimines with an Unprecedented Substrate Scope. Chemical Communications 2007, 2977.

148. de Vries, T. S.; Prokofjevs, A.; Vedejs, E. Cationic Tricoordinate Boron Intermediates: Borenium Chemistry from the Organic Perspective. Chemical Reviews 2012, 112, 4246. 149. Kolle, P.; Noth, H. The Chemistry of Borinium and Borenium Ions. Chemical Reviews 1985, 85, 399. 150. Piers, W. E.; Bourke, S. C.; Conroy, K. D. Borinium, Borenium, and Boronium Ions: Synthesis, Reactivity, and Applications. Angewandte Chemie International Edition 2005, 44, 5016. 151. Shoji, Y.; Tanaka, N.; Mikami, K.; Uchiyama, M.; Fukushima, T. A Two-Coordinate Boron Cation Featuring C–B+–C Bonding. Nature Chemistry 2014, 6, 498.

152. Farrell, J. M.; Hatnean, J. A.; Stephan, D. W. Activation of Hydrogen and Hydrogenation Catalysis by a Borenium Cation. Journal of the American Chemical Society 2012, 134, 15728. 153. Prokofjevs, A.; Kampf, J. W.; Vedejs, E. A Boronium Ion with Exceptional Electrophilicity. Angewante Chemie International Edition 2011, 50, 2098.

154. Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. Asymmetric Reduction of Aromatic Ketones with the Reagent Prepared from (S)-(-)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol and Borane. Journal of the Chemical Society of Japan, Chemical Communications 1983, 469. 155. Corey, E. J.; Bakshi, R. K.; Shibata, S. Highly Enantioselective Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and Synthetic Implications. Journal of the American Chemical Society 1987, 109, 5551. 156. Vries, T. S.; Prokofjevs, A.; Vedejs, E. Cationic Tricoordinate Boron Intermediates: Borenium Chemistry from the Organic Perspective. Chemical Reviews 2012, 112, 4246.

157. Lindsay, D. M.; McArthur, D. The Synthesis of Chiral N-Heterocyclic Carbene–Borane and– Diorganoborane Complexes and Their use in the Asymmetric Reduction of Ketones. Chemical Communications 2010, 46, 2474. 158. Horn, M.; Mayr, H.; Lacote, E.; Merlin, E.; Deander, J.; Wells, S.; McFadden, T.; Curran, D. P. N-Heterocyclic Carbene Boranes are Good Hydride Donors. Organic Letters 2012, 14, 82. 159. Taniguchi, T.; Curran, D. P. Silica Gel Promotes Reductions of Aldehydes and Ketones by N-Heterocyclic Carbene Boranes. Organic Letters 2012, 14, 4540.

160. Chase, P. A.; Jurca, T.; Stephan, D. W. Lewis Acid-Catalyzed Hydrogenation: B(C6F5)3-

Mediated Reduction of Imines and Nitriles with H2. Chemical Communications 2008, 1701. 161. Farrel, J. M.; Hatnean, J. A.; Stephan, D. W. Activation of Hydrogen and Hydrogenation Catalysis by a Borenium. Journal of the American Chemical Society 2012, 134, 15728. 162. Farrel, J. M.; Posaratnanathan, R. T.; Stephan, D. W. A Family of N-heterocyclic Carbene- Stabilized Borenium Ions for Metal-Free Imine Hydrogenation Catalysis. Chemical Science 2015, 6, 2010. 163. Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, M. Z.; Welch, G. C.; Ullrich, M. Metal-Free Catalytic Hydrogenation of Polar Substrates by Frustrated Lewis Pairs. Inorganic Chemistry 2011, 50, 12338.

164. Stephan, D. W.; Erker, G. Frustrated Lewis Pairs II; Expanding the Scope; Springer Heidelberg: New York, 2013. 165. de Oliveira Freitas, L. B.; Eisenberger, P.; Crudden, C. M. Mesoionic Carbene−Boranes. Organometallics 2013, 32, 6635.

166. Jonnalagadda, S. C.; Suman, P.; Patel, A.; Jampana, G.; Colfer, A. Allylboration. In Boron Reagents in Synthesis; Coca, A., Ed.; American Chemical Society, 2016; pp 67 - 122. 167. Manas, M. G.; Sharninghausen, L. S.; Balcells, D.; Crabtree, R. H. Experimental and Computational Studies of Borohydride Catalyzed Hydrosilylation of a Variety of C=O and C=N Functionalities Including Esters, Amides and Heteroarenes. New Journal of Chemistry 2014, 38, 1694.

Chapter 2

Investigations into Boro-Ion Catalysis

2.1 Mesoionic Carbene-Borenium Ion Catalyzed Hydrogenations

2.1.1 Introduction As previously discussed, borenium cations possess a Lewis acidity comparable to perfluorinated aryl boranes, an unsaturated coordination sphere, and relatively high stability as compared to other boro-cations, making them ideal targets to investigate as catalysts for FLP-type chemistry. (1) (2) Previous studies in the Crudden group looked into the properties of 1,2,3- triazolylidene-based carbenes, the mesoionic cousins of NHCs, as ligands for transition metal catalysis. (3) (4) Conducted by former doctoral student Eric Keske, the investigations into these mesoionic carbenes (MICs) focused on their incorporation into pincer-type ligands, the coordination of MICs to a variety of metals including Rh, Ir, Ag, Pd and the assessment of these metal-MIC complexes, specifically Pd complexes, as catalysts for the Mizoroki-Heck reaction. (5)

Although conditions were found under which the reaction proceeded, further investigations showed that elemental mercury poisoning of the reaction led to complete reaction inhibition, indicating that the Pd-MIC complex was likely not the active catalyst. (5) We thereafter became interested in using

MICs as ligands for other metals specifically for boron. MICs have been shown previously to have even higher σ-donation capacities than NHCs, leading us to suspect that coordination to boranes would result in increased C–B strength and increased B–H bond reactivity. (6) (7) (8) This was confirmed by studies, conducted by postdoctoral fellow Patrick Eisenberger and doctoral exchange student Luiza Baptista de Oliveira Freitas, who assessed the ability of MICs to coordinate borane and the reducing power of the resulting MIC-borane. (9) A facile one-pot procedure was devised to produce a variety of MIC-boranes, which were found to be more hydridic than their NHC congeners (9) due to the increased σ-donation capacity of MICs. (7) The good σ-donation capacity

of MICs led us to suppose they would be excellent ligands for the stabilization of borenium ions, which, as inspired by the work of Stephan et al., could be used as FLP hydrogenation catalysts.

(173)

2.1.2 Non-selective MIC-Borenium Ion Hydrogenation Results and Discussion In order to investigate whether MIC-borenium ions could be used as FLP-type hydrogenation catalysts, we first developed a library of MIC-9-borabicyclo[3.3.1]nonane (9-BBN) and NHC-9-BBN adducts (2-1x), Figure 2-1. Initial catalyst development was conducted by postdoctoral fellow Patrick Esienberger who synthesized all the carbene-borane adducts shown in

Figure 2-1. Patrick Esienberger also performed the catalyst optimization as discussed below. (11)

Figure 2-1 Carbene borane adducts investigated as hydrogenation catalysts. Dipp = 2,6- diisopropylphenyl

With the above library in hand, investigations into catalyst activity could begin. The carbene-borenium ions (2-3 and 2-4) were generated from the corresponding carbene-boranes (2-

+ - 1, 2-1), Figure 2-2, by treatment with an equimolar amount of Ph3C B(C6F5)4 prior to the addition of substrate and charging of the reaction vessel with dihydrogen. Initial optimizations utilized imine

2-5a as a test substrate for hydrogenation, as we suspected the steric bulk alpha to the nitrogen 55

would diminish catalyst coordination/inactivation and the unhindered aldimine carbon would allow for facile nucleophilic attack.

Figure 2-2 Carbene-borenium ion generation from carbene-borane

Isosteric catalysts 2-1b and 2-2b were prepared to permit a direct comparison between

NHC- and MIC-borenium ions, Table 2-1. The NHC-borenium ion 2-4b afforded only a 16 % conversion of 2-5a at 38 atm dihydrogen for 4 hours, at a loading of 10 mol %, entry 1. By comparison, MIC-borenium ion 2-3b gave 50 % conversion at the same concentration and pressure

(Table 2-1, entry 2), indicative of the higher reactivity of MIC-stabilized borenium ions. Steric effects were further assessed with borenium ion 2-3a, possessing only one flanking phenyl group.

To our delight, borenium ion 2-3a proved the most active giving the complete reduction of aldimine

2-3a with as little as 22 atm of dihydrogen after 4 hours (Table 2-1, entry 3). Complete reduction of imine 2-5a was achieved after 19 h with as little as 1 atm of hydrogen (Table 2-1, entry 4), showing that efficient reduction could be achieved at ambient pressures with increased reaction times.

Table 2-1 Borenium ion catalyzed imine hydrogenation optimization.

Having developed reaction conditions that could be conducted using standard glassware under ambient conditions, we then turned to more difficult to reduce substrates. Encouragingly, catalyst

2-3a was able to hydrogenate 2-5b under the previously developed conditions at 10 mol % catalyst loading and 1 atm dihydrogen (Table 2-1, entry 5). (11) The desired product was isolated in 87 % yield. Even at 5 mol %, complete conversion was obtained within 23 h (Table 2-1, entry 6), however a further reduction to 2.5 mol % loading gave only 40 % product after 24 h (Table 2-1, entry 7). Further screening of the other carbene-boranes from our library, Figure 2-1, showed no significant advantage in catalytic activity over borenium ion 2-3a at 5 mol % catalyst loading and

1 atm dihydrogen. Although not superior, catalyst 2-3c, possessed similar catalytic activity to 2-3a.

The synthesis of 2-3c results in a distribution of difficult to separate regioisomers, therefore, it was decided to use catalyst 2-3a for investigations into the substrate scope of this reaction.

Having found the optimum hydrogenation catalyst from our library of carbene-boranes we then sought to investigate the scope and limitations of the reduction, Table 2-2. This following 57

work, unless otherwise stated, was conducted by the author. Disappointingly, it was found that the reaction was sensitive to substrates lacking sufficient steric bulk alpha to the imine nitrogen. As such, imines possessing an N-Bn group in place of an N-Ph group, e.g. ketamines 2-5c and 2-5d, were hydrogenated sluggishly if at all under 1 atm of dihydrogen, Table 2-2 entries 2 and 3. In the case of ketamine 2-5d, it was found that our original conditions of 1 atm of hydrogen gas for 18 h gave only 26% conversion. Increasing the hydrogen pressure to 102 atm gave quantitative conversions Table 2-2 entry 3. Unfortunately, even hydrogen pressures of 102 atm were insufficient to promote the hydrogenation of 2-5c, Table 2-2 entry 2.

Table 2-2 Borenium ion 2-3a catalyzed imine hydrogenation.

The sluggish reduction of imines lacking sufficient steric bulk alpha to the nitrogen centre, such as 2-5d, was not entirely surprising. NMR analysis of the reaction mixture by Patrick

Eisenberger led to the conclusion that four-coordinate boronium ions are the major products in mixtures of imines and borenium ions. In the case of a mixture between borenium ion 2-2a and imine 2-5b, the catalyst boron signal is observed to shift downfield from 70.8 ppm to 12.5 ppm, the latter indicative of 4-coordinate boronium ions such as 2-7b, Figure 2-3. The formation of boronium ion 2-7b indicates an unproductive equilibrium between the catalytically active borenium ion and an inactive boronium ion species.

Figure 2-3 Proposed catalytic cycle and off-cycle equilibrium for MIC-borenium ion catalyzed hydrogenations It is worth noting however that since the reduction of 2-5b proceeds readily, there must still be enough free borenium ion to allow for catalytic turnover. Substrates which bind too tightly to the borenium ion result in a situation where no catalyst is able to form the encounter complex required for dihydrogen splitting, leading to the complete shutting down of the catalytic cycle at worse, or dramatically reducing the amount of active catalyst in solution, at best. (175) 60

Imines with the benzhydryl protecting group were then assessed (2-5e and 2-5f, Table 2-2 entries 4 and 5). To our delight, the increased steric bulk adjacent to the nitrogen centre allowed for the reduction of 2-5e, albeit at higher dihydrogen pressures, mirroring ketamine 2-5d. By further increasing the steric bulk around the nitrogen centre, as in the case of 2-5f, we were able to again use hydrogen pressures closer to ambient conditions (5 atm), Table 2-2 entry 5. Substrates lacking sufficient steric bulk proximate to the nitrogen centre coordinate more strongly to the borenium ion, resulting in a lower concentration of active catalyst in solution. We were able to compensate for this by elevating the reaction dihydrogen pressure, resulting in a higher dihydrogen concentration in solution, increasing the rate of this bimolecular reaction.

It was then decided to assess the functional group compatibility of the borenium ion catalyst. The hydrogenation of our standard imine 2-5b was performed concurrently with 1 equivalent of the ketone fenchone (2-8), Eq. 2-1, at 102 atm of hydrogen. After 18 hours, 1H NMR analysis indicated that 2c was produced with a conversion of 82 %, with no observable reduction of the ketone. As such, it was determined that the ketone is not a competitive substrate for the hydrogenation, though given that the reduction of 2-5b proceeds to completion at 1 atm dihydrogen after 19 h in the absence of fenchone, the ketone likely coordinates the borenium ion resulting in an overall reduction of the catalytic activity.

(Eq. 2-1)

Next we examined the hydrogenation of N-heterocycles using MIC-borenium ion catalyst

2-3a. Using previously developed conditions, Patrick Eisenberger showed that catalyst 2-3a was able to hydrogenate a variety of 2- and 8-arylated quinolines to their corresponding 1,2,3,4- tetrahydroquinoline derivatives, 2-10a-f Table 2-3. 61

Table 2-3 Borenium ion 2-3a catalyzed quinoline hydrogenations

Quinoline itself and 3-arylated quinolines were unable to be hydrogenated, even at 102 atm of dihydrogen. The following results were obtained by the author. The relatively sterically unencumbered 8-methyl quinoline (2-9g) was fully reduced with as little as 5 atm dihydrogen for

18 hours, Table 2-4. Again, the need for higher dihydrogen pressures with less sterically encumbered substrates is most likely due to strong substrate coordination to the borenium ion decreasing that amount of free catalyst able to enter the catalytic cycle, necessitating a higher dihydrogen concentration to allow for an appreciable catalytic turnover of this bimolecular reaction.

Table 2-4 Borenium ion 2-3a catalyzed N-heterocycle hydrogenation.

We then sought to further push the scope of N-heterocycles capable of being hydrogenated by catalyst 2-3a to the more challenging pyridines, specifically the 2,6-disubstituted derivatives 2- 63

9i-k. To our delight, it was indeed possible to hydrogenate a variety of pyridines to their corresponding piperidines, exclusively as the cis diastereisomers. Although higher pressures were required to hydrogenate the pyridine substrates, the conditions were nevertheless significantly milder than previously reported FLP-type systems (100 °C, 50 atm H2, 20 h) used in the reduction of this class of substrates. (13)

Finally, we also wanted to investigate extended π-systems such as 9,10-phenanthroline (2-

9h). Elevated pressures were required for the hydrogenation of 2-9h, and after 18 h, only the partially reduced product, 2-10h, was observed with no over reduction. When longer reaction times were used in an attempt to improve the conversion to 2-9h, reduction of the second heterocycle was observed, however the partially reduced products proved inseparable by column chromatography.

2.1.3 Enantioselective MIC-Borenium Ion Hydrogenation Results and Discussion Having developed a robust MIC-borenium ion catalyst capable of hydrogenating a variety of substrates, we next set out to develop an enantioselective variant. There are three distinct components of the catalyst that can be varied to introduce asymmetry: 1) carbene, 2) counterion, and 3) borenium ion, Figure 2-4. To maximize the chances of successfully developing an enantioselective MIC-borenium ion catalyst, it was decided to develop a chiral version of each distinct component. Fellow Crudden group member Joshua Clarke prepared a library of chiral

BINAP-based phosphate and thiophosphate counter ions (2-11), Patrick Esienberger synthesized a chiral BINAP-based MICs (2-12) and I examined chiral boranes, specifically the 9- borobicyclo[3.3.2]decanes (9-BBD, 2-13). The following discussion will only include my work on

9-BBDs.

Figure 2-4 Components of a carbene-borenium ion hydrogenation catalyst

First described in 2005 (14), BBDs (2-13) are structural variants of 9- borabicyclo[3.3.1]nonane (9-BBN), which was used as the borenium ion component in our first generation of catalysts (2-1, Figure 2-1). 9-Borabicyclodecanes, are synthesized via the insertion of a diazo-derived carbene (2-15) into the C–B bond of B-Methoxy-9-BBN (2-14), They possess a

[3.3.2] bicyclic structure with a chiral centre alpha to boron, Scheme 2-1. (15)

Scheme 2-1 Synthesis of 9-borobicyclo[3.3.2]decanes

The structural similarity between 9-BBDs and 9-BBN, in addition to the fact that 9-BBDs possess a chiral centre alpha to the boron, made us suppose 9-BBDs would be a promising target to investigate as potential chiral borenium ion catalysts. (16) In the course of their studies,

Soderquist et al. demonstrated that 9-BBDs are ideally suited for the highly regio-, diastereo-, and enantioselective allyl-, (17) crotyl-, (14) methoxyallyl-, (18) propargyl-, (19), and allenylboration

(20) of aldehydes, (14) ketones, (17) aldimines, (21) and ketamines (22) as well as the region- and enantioselective hydroboration of alkenes (15). For these reasons, it was felt that 9-BBDs warranted investigation as chiral boranes in our efforts to achieve enantioselective hydrogenations.

Following the procedure reported by Soderquist in 2008, 9-BBDs 2-16a and 2-16b were synthesized in moderate to good yields from B-methoxy-9-BBN, Scheme 2-1. (15) Unfortunately, one of the major drawbacks in the applicability of 9-BBDs is that thus far only racemic syntheses of this class of compounds have been reported.[10] – [18] However, resolution of the borinic ester can be achieved relatively easily by exchanging the B-methoxy substituent for an enantiopure amino alcohol, such as N-methyl-pseudoephedrine, (2-17). The resulting borinic ester 2-18a forms selectively, and can be subsequently collected after recrystallization from hexanes Eq. 2-2 (15)

(Eq. 2-2)

Enantiopure (S)-2-18a was isolated after the first round of crystallization in 21 % overall yield from the initial starting material, equivalent to 42 % recovery of the S-enantiomer of 2-16a. An attempt was made to recover more enantiopure (S)-2-18a by a second crystallization, unfortunately moisture was able to enter the system resulting in the degradation of the starting material and product.

With 2-18a in hand, our next goal was to attempt to produce 9-BBD analogues of the MIC catalysts (2-1) previously discussed. Initial attempts at synthesizing carbene-bound 9-BBD boranes utilized racemic 9-BBDs. To produce the MIC-BBD adducts, it was first necessary to convert 9-

BBD 2-16a to its lithium borohydride analogue, 2-19a Scheme 2-2. Once synthesized, 2-19a could be subjected to hydride abstraction generating the necessary borane (2-14), Scheme 2-3. Our first approach, following the method reported by Soderquist et al., (15) utilized in situ generated

LiAlH3OEt and failed resulting in only recovered starting material. A slightly modified procedure was developed in which 2-16a was treated with LiAlH4 in THF at ambient conditions, resulting in the clean formation of lithium borohydride 2-19a, Scheme 2-2.

Scheme 2-2 Synthesis of lithium dihydro-9-borabicyclodecanes

Treatment of 2-19a with one equivalent of iodomethane afforded borane 2-13a, the production of which could be followed visually by gas evolution (methane). Following hydride abstraction, 2-13a was filtered and concentrated in vacuo, to remove reaction by-products and unreacted starting material. Borane 2-13a was used without further purification. Given the success we had with 1,3-diphenyl-1H-1,2,3-triazolium tetrafluoroborate (Ph2MIC, 2-20) in our previous

hydrogenation studies we decided to use this MIC for our initial attempts synthesizing chiral carbene-boranes, Scheme 2-3. (11)

Scheme 2-3 Synthesis of MIC-BBDs

Treatment of 2-20 with sodium hexamethyldisilazane (NaHMDS) in the presence of 2-13a at room temperature afforded carbene-borane adduct 2-21a as the sole product by NMR.

Disappointingly however, the isolation of 2-21a proved quite difficult, with the product often degrading into a black unidentifiable material, regardless of the crystallization condition used. In addition, the synthesis of 2-21a proved to be erratic and often irreproducible, which, in combination with a difficult isolation, resulted in 2-21a only being obtained in small quantities. Modifications to the reaction procedure, including lowering the reaction temperature, trying alternative bases

+ - (NaH), reaction solvents (PhMe), carbenes (1,3-dimethylimidazolium, Me2Imd Br , 2-22), and recrystallization conditions, all yielded the same result with no improvement over the initial conditions, Table 2-5.

Table 2-5 Attempted synthesis of carbene-9-BBDs

The erratic nature of the adduct formation may be due to the increased steric bulk that 9-BBDs possess alpha to the boron centre resulting in unfavorable steric interactions between the BBD and carbene contributing to its instability, Figure 2-5.

Figure 2-5 Unfavorable interactions between MIC and BBD

With the little amount of carbene-borane 2-21a that we were able to obtain the hydrogenation of 2-5a was attempted (Eq. 2-3). Unfortunately no reduced product could be detected.

(Eq. 2-3)

Due to the difficulty encountered using 2-20 as the ligand we explored the use of less bulky carbenes, specifically the NHC 1,3-dimethylimidazolium (Me2Imd, 2-22), Eq. 2-4, to produce 9-

BBD-based catalysts. The synthesis of 2-23a, identified by the appearance of a doublet at -14.1 ppm in the 11B NMR spectrum, proved no less erratic, suffering the same isolation problems previously observed for MIC-borane 2-15a, see Table 2-5 entries 6 & 7.

(Eq. 2-4)

Despite being unable to purify 2-23a, an attempt was made to hydrogenate 2-3a using the crude reaction mixture from, Eq. 2-5. As was previously the case, no reduced product was observed by

NMR. The lack of conversion may be as a result of inseparable impurities or the degradation of the compound.

(Eq. 2-5)

Thus, 9-BBD-based compounds appear to be ill-suited as borenium ion catalysts, despite our initial hopes. However, these investigations are by no means exhaustive and further investigation into other carbenes or ligands to stabilize the borenium ion are on-going. Furthermore, it may be prudent to investigate other chiral boranes as borenium ion precursors such as the

Masamune borane (trans-2,5-dimethylborolane, 2-24), possessing a C2 symmetric structure, which may prove advantageous, Figure 2-6. (23) Furthermore with the lack of success we had in generating 9-BBD-based borenium ions, we decided to investigate other uses for these molecules, specifically as nucleophilic catalysts, which is discussed in section 2.2.2.

Figure 2-6 Masamune Borane 2-24

2.1.4 Investigations into Borenium Ion Catalyzed Amine Racemization During the course of our studies into enantioselective borenium ion catalyzed hydrogenations we became concerned with the facility of hydride abstraction by MIC-borenium ions complexes and whether or not this would lead to racemization of enantioenriched centres.

Hydride abstraction from sp3 C–Hs alpha to nitrogen by strong Lewis acids is not without precedent. Previously, Stephan et al. in 2011 showed that tris(pentaflurophenyl)borane (BCF) can catalyze the hydrogenation of imines and N-heterocycles via a transfer hydrogenation using secondary amines as the dihydrogen equivalent. (24) In an elegant experiment, BCF was shown to completely racemize 2-25, resulting in a 1:2 ratio of the meso to optically active compound,

Scheme 2-4. As well, the stoichiometric reaction between 2-25 and BCF showed production of B-

H-tri(pentaflurophenyl)borate anion. Both of these results are indicative of a hydride abstraction from 2-25. (24)

Scheme 2-4 Stephan’s BCF catalyzed racemization of bis[(R)-1-phenylethyl]amine (24) 71

The BCF transfer hydrogenation reaction was further expanded upon by Osetreich who showed that 1,4-cyclohexadienes could also be used as a dihydrogen equivalent for the reduction imines and N-heteroaromatics. (187) BCF and carbene-borenium ions possess similar Lewis acidities, as determined by comparison of acceptor numbers (AN) obtained using the Gutmann-

Beckett method, (26) (27) BCF 79.8 AN (28) vs. Ph2MIC-9BBN 78.9 AN, (11) and hydride

i affinities, BCF -41.0 kcal/mol vs. Pr2Imd-9BBN -41.6 kcal/mol. (29) Therefore, it is not unreasonable to consider that our borenium ions may be also capable of a hydride abstraction resulting in amine racemization.

In order to test if borenium ions are capable of hydride abstraction from N-alpha sp3-C–H bonds, it was decided to repeat Stephan’s epimerization experiment of bis[(R)-1- phenylethyl]amine, 2-25, using our borenium ion catalyst 2-3a. The BCF catalyzed epimerization of 2-25 was conducted under the same conditions for a direct comparison of the two Lewis acids.

Mirroring Stephan's previous results, (24) 10 mol % of BCF was mixed with 2-25 in 0.5 mL CD2Cl2 in a J-young tube and monitored by 1H NMR. After 20 minutes, a ratio of 1:9 meso to racemic 2-

25 is reached, and in less than 16 h at room temperature, the complete racemization of 2-25 is reached with an equilibrium ratio of 1:2 as expected, Figure 2-7. The ratio of 1:2 represents a 1:1:1 ratio of the three possible isomers of 2-25; (R,R), (S,S), and (meso) where the (R,R) and (S,S) isomers of 2-25 are enantiomers and are thus chemically equivalent manifesting as a single peak at

3.65 ppm in the NMR spectrum. The (meso) isomer is observed at 3.92 ppm and represents the

(R,S) and (S,R) isomers of 2-25, however as these isomers possess an internal plane of symmetry, they are in fact configurationally identical and are single compound.

Figure 2-7 BCF catalyzed racemization of 2-25 followed by 1H NMR

In contrast to BCF, our MIC-borenium ion 2-3a gave virtually no epimerization under conditions identical to those used for BCF, Figure 2-8. Only a minor epimerization, of 1:46 meso to racemic corresponding to 4 % racemization, of 2-25 was detected after 16 h. Only after heating at 65 °C for a period of 26 h was 50 % racemization observed. These results indicated that enantioselective carbene-borenium ion hydrogenation catalysts may be a more suitable option than

BCF-derived catalysts as our results suggest hydride abstraction is only a minor side reaction with borenium ion catalysts. The low hydride abstraction rate of our MIC-borenium ion may be a result of the strong σ-donating ability of the MIC ligand providing us with an exceptionally stabile borenium ion. (6) (7) (8)

Figure 2-8 1H NMR analysis of borenium ion, 2-3a, catalyzed racemization of 2-25

2.2 Introduction Boro-Ion Catalyzed Hydrosilylation

Having investigated the applicability of borenium ions as Lewis acids for FLP-type hydrogenations, we endeavored to investigate what other bonds could activated by our catalyst.

Largely inspired by the ground-breaking of the Piers lab (30) (31) (32) (33) we became interested in the applicability of borenium ions towards Si–H activation. Again, given the similar Lewis acidity and hydride affinities between perfluoroaryl borane and borenium ions, we believed it should be possible to activate silanes with our borenium ion catalyst. (28) (11) Furthermore, silanes possess several advantages over dihydrogen given that they are generally liquid at room temperature and relatively stable, resulting in easier handling compared to explosive dihydrogen gas. Surprisingly, literature research revealed only two brief examples of borenium ion-catalyzed hydrosilylation reactions. (34) (35) 74

The first example of a borenium ion-catalyzed hydrosilylation was by Jäkle et al. in 2013 who reported the chiral ferrocene based borenium ion 2-26 and used it catalytically for the reduction of acetophenone. The hydrosilylation of acetophenone by 2-26 proceeded slowly with only 60 % conversion by 1H NMR after 12 h and only achieved 20 % enantiomeric excess. Unfortunately no further investigation into its catalytic activity was reported. (34) Shortly after Jäkle, Denmark et al. reported the second example of a borenium ion-catalyzed hydrosilylation using borenium ion 2-27.

(35) In their report, Denmark et al. demonstrated that the 9-BBN-based borenium ion catalyst 2-27 was able to catalyze the hydrosilylation of a variety diarlycarbonyls and that it activated silanes via a sigma complex, similar to that observed in the case of BCF-catalyzed hydrosilylations. (35) (30)

(31) (36)

Scheme 2-5 Previous reports of borenium ion catalyzed hydrosilylation by Jäkle and Denmark (34) (35)

Overall, the several advantages of silanes over dihydrogen and the lack of in depth research into borenium ion-catalyzed hydrosilylation reactions prompted us to further investigate this topic. 75

2.2.1 Mesoionic Carbene-Borenium Ion Catalyzed Hydrosilylation Results and Discussion We began our investigations into borenium ion-catalyzed hydrosilylations in conjunction with visiting student Ryoto Kojima and post-doctoral fellow Patrick Eisenberger. Ketamine 2-5b was chosen as a test substrate as we previously showed it be highly susceptible to borenium ion catalyzed hydrogenation. Ketones were not investigated due to concerns of catalyst inhibition as a result of boron’s high oxophilicity. Furthermore, our initial investigations utilized catalyst 2-1a due to the success we had using it as a hydrogenation catalyst.

To begin our investigations, conditions were chosen similar to those previously reported by Jäkle and Denmark: 10 mol % catalyst in CD2Cl2 with 1.1 equivalents silane. (34) (35) Reactions were done, unless otherwise noted, on a 0.25 mmol scale with 0.5 mL solvent in a J-young tube to allow for monitoring by 1H NMR. In our initial attempt at the hydrosilylation of 2-5b, we employed triethylsilane like the previously hydrosilylations reported by Jäkle and Denmark, Table 2-6 entries

1 and 2. (34) (35) As we suspected, borenium ion 2-3a was able to effect the hydrosilylation of 2-

5b at 10 % catalyst loading at room temperature. However to our surprise, the reaction proceeded quite slowly, achieving only 18 % conversion to 2-28b at room temperature after 19.5 h, Table 2-6 entry 1. The reaction was then heated at 60 °C for a period of 23 h, resulting in a 61 % conversion to product, Table 2-6 entry 2. This was surprising as Denmark’s investigation into the borenium ion catalyzed hydrosilylation of ketones gave complete reduction in as little as 10 min for some cases, with the longest reaction time being 3 h. (35) This prompted us to investigate other silanes to see if the reaction rate could be accelerated, specifically employing less bulky silanes as we suspected the sterics and non-rigid structure of triethylsilane may be impeding silane activation with our bulky catalyst.

Table 2-6 Silane optimization for borenium ion catalyzed hydrosilylation.

Further screening of silanes supported our hypothesis that sterics were a factor in silane activation, revealing the general trend that less bulky and less substituted silanes were able to affect hydrosilylation considerably faster. When using phenyldimethylsilane, the hydrosilylation of 2-5b proceeded considerably faster in comparison to triethylsilane, achieving 64 % conversion after 2 h

(Table 2-6, entry 3) and near complete conversion after 3.5 h (Table 2-6, entry 4). Phenyl- and diphenylsilane (Table 2-6, entries 6 and 7) were the fastest, resulting in complete conversion of 2-

5b faster than could be measured accurately at 1 mol % catalyst loading. Phenylsilane proved a competent enough hydride donor that catalyst loadings could be reduced to 0.1 mol % and complete conversion was still achieved in as little as 1 h at this low loading. Reduced reaction times with less bulky silanes is indicative of the easier formation of a borenium ion σ-complex (Figure 2-9, A or facilitation of the subsequent H–Si splitting (Figure 2-9, A → B). 77

Figure 2-9 Proposed mechanism for borenium ion catalyzed hydrosilylation

Having found suitable conditions and a silane capable of affecting hydrosilylation at a reasonable rate, we decided to investigate the scope of this reaction, shown in Table 2-7. We found that the hydrosilylation of a wide variety of aromatic aldimines and ketamines proceeded readily.

In most cases, using 1 mol % catalyst proved insufficient, resulting in either sluggish hydrosilylation of the substrate, or no hydrosilylation at all. In these cases, the catalyst loading was increased to 3 or 5 mol %. Our borenium ion catalyzed hydrosilylation proved tolerant towards esters (Table 2-7, entry 5), which was not observed in our previous borenium ion catalyzed hydrogenations. (11). Nitro- (Table 2-7, entry 4) and trifluoromethyl (Table 2-7, entry 3) groups were also compatible with our catalytic system, despite BCF/Et3SiH being shown to effect the reduction/hydrodefluorination of both these group. (37) (38)

Table 2-7 Borenium ion catalyzed imine hydrosilylation substrate scope.

Table 2-8 Borenium ion catalyzed imine hydrosilylation substrate scope.

Double bounds were also tolerated, with no evidence of hydrosilylation of the double bond (Table

2-8, entry 2), highlighting the power of this metal-free hydrosilylation. It should be noted the

reduced product of 2-5m required N-tosylation for isolation to avoid product loss (Table 2-8, entry

2). In contrast to our results with borenium ion catalyzed hydrogenations, (11) requirements for steric bulk alpha to the imine nitrogen were less pronounced as evident by the rapid reduction of

N-benzyl compounds 2-5e and 2-5o (Table 2-8, entries 1 and 4). (11) Finally N-sulfonyl groups were also tolerated under our reaction conditions (Table 2-7, entry 3), which is synthetically interesting, as it provides a pathway for the synthesis of primary amines after sulfonyl deprotection.

(39)

Having investigated a wide range of imines we decided to look into the hydrosilylation of

N-heterocycles using our catalyst system. The hydrosilylation of quinolines using BCF has been previously reported by Chang et al. who observed bis-hydrosilylation of the nitrogen containing ring to give the 3-silylated-tetrahydroquinoline. (40) With this in mind, we first investigated the hydrosilylation of 8-methylquinoline, 2-31 Table 2-9. The complete reduction of the nitrogen- containing heterocycle to the tetrahydroquinoline ring was expected as was observed by Chang et al. (40) and in our previous investigations into borenium ion catalyzed quinoline hydrogenation

(11). However, in contrast to these reports, only the mono hydrosilylation of the nitrogen- containing ring was observed. Initial reduction of 8-methylquinoline proceeded rapidly, giving approximately 73 % conversion to the 1,4-reduced product (2-32) with 7 % conversion to the 1,2- reduced product (2-33) after 1 hour, Table 2-9, as determined by 1H NMR. This rapid formation of the 1,4-reduced product was also observed by Chang et al. and is most likely a due to steric considerations, the 1,2-reduction being sterically encumbered after the silylation of the quinoline nitrogen. (40)

Table 2-9 Borenium ion catalyzed hydrosilylation of 8-methylquinoline.

In an effort to produce tetrahydro-8-methylquinoline, the hydrosilylation of 2-31 was allowed to proceed for a period of 48 hours with periodic analysis by 1H NMR. Unfortunately, no fully reduced product could be detected. Instead, the ratio of 2-33 to 2-32 increased, eventually resulting in a 10:11 ratio of 2-33 to 2-32 of the partially reduced product. Increasing the reaction time to 48 h resulted in a complex mixture unidentifiable by 1H NMR. Similar results were observed when the reaction was conducted at elevated temperature (65 °C) as well as with excess or sub- molar equivalents of silane. Additional attempts at the isolation of the partially reduced 8- methylquinoline met with little success. At this point, fellow Crudden group member Joshua Clarke began to investigate this reaction and found that the partially reduced quinoline could be captured with an aldehyde giving the 2,3-disubstituted tetrahydroquinoline, Scheme 2-6. This is currently under further investigation by Joshua Clarke.

Scheme 2-6 Partially reduced quinoline capture by aldehyde.

2.2.2 Borohydride Catalyzed Hydrosilylation of Carbonyl Compounds Thus far, we have described the use of boron compounds as electrophilic catalysts to induce bond activation. During our investigations into electrophilic boro-catalysts, we became interested in the prospect of using boron compounds as nucleophilic catalysts. In early 2014, Crabtree et al. reported that simple borohydrides, such as LiHBEt3, could be used catalytically for the hydrosilylation of carbonyl compounds, imines and N-heterocycles. (202) With computational and experimental support, Crabtree proposed a novel mechanism, where the borohydride acts as a nucleophilic catalyst. In the proposed catalytic cycle, initial reduction of the carbonyl by the borohydride (2-35 → 2-36) ultimately results in an alkoxide-activated silane, which participates in a hydride transfer to the free borane regenerating the catalyst (2-37 → 2-38, Figure 2-10).

Figure 2-10 Proposed mechanism of borohydride catalyzed carbonyl hydrosilylation

Based on the above mechanism, we reasoned that a chiral borohydride, such as the 10-

BBDs we previously invested for enantioselective borenium ion hydrogenations (see section 2.1.3), could be used as an enantioselective hydrosilylation catalyst. As no dialkyl borohydrides were examined in Crabtree’s initial publication, (202) we first decided to investigate sodium 9-

boratabicyclo[3.3.1]nonane (Na-9-BBN-H2) as a surrogate for the BBDs to assess the potential of these types of compounds as nucleophilic hydrosilylation catalysts. (202) In accordance with

Crabtree’s report, catalytic amounts of the borohydride Na-9BBN-H2 with 1.5 hydride equivalents of PMHS led to the facile reduction of a variety of aldehydes and ketones, Table 2-10.

Table 2-10 Substrate scope of achiral borohydride catalyzed hydrosilylation

Bulkier ketones and esters required longer reaction times and elevated temperature to achieve complete reduction. In contrast to Crabtree’s report, Na-9BBN-H2 was not able to catalyze the reduction of amides, imines or nitriles even at elevated temperatures (Table 2-10 entries 3,8,9).

The difference in reactivity observed may be as a result of the poorer hydride donation ability of

Na-9BBN-H2 (ΔGH- = 33 kcal/mol) as compared to LiHBEt3 (ΔGH- = 24 kcal/mol). (42) Having shown that dialkyl borohydrides work as nucleophilic hydrosilylation catalysts, we next turned our attention to our BBD borohydrides. Using our racemic catalyst 2-19a, we compared its reactivity to Na-9BBN-H2, and found it to be considerably less reactive, achieving only 10 % conversion after 2 h using 5 mol % catalyst (Table 2-11, entry 1) while Na-9BBN-H2 gave complete conversion after 2 h (Table 2-11, entry 2).

Table 2-11 Optimization for BBD borohydride catalyzed hydrosilylation

Reduced catalytic activity may be a result of slower Lewis acid exchange, as per Crabtree’s proposed mechanism (2-35 → 2-36, Figure 2-10), due to the increased steric bulk of the BBD framework. However it could also be due to a lower hydride donating ability of the BBD as a result of the electron withdrawing nature of the phenyl ring, or a combination of these factors. (43) The

lower catalytic activity of 2-19a could however be easily ameliorated by simply doubling catalyst loading (Table 2-11, entry 4).

With catalytic conditions in hand capable of affecting carbonyl reduction in a practical time, we then began to investigate the reaction using the enantioenriched catalyst (S) – 2-19a. The previously developed conditions were used for the reduction of 2-39b, and were found to give 14

% enantiomeric excess of the product as determined by chiral SFC (Table 2-12, entry 1).

Table 2-12 Condition screening for enantioenriched BBD borohydride catalyzed hydrosilylation

The less polar solvent toluene resulted in a greater e.e., however with lower yields, entry 2. Altering the hydride source to phenylsilane (entry 3) resulted in rapid ketone reduction, however, at the cost of poor enantioselectivity. The use of a less reactive silane resulted, again in the improvement of the enantioenrichment of the reaction, but still considerably lower than what may be consider synthetically useful. Although these results are somewhat disappointing, nevertheless further investigations into this reaction seems warranted, specifically the further testing of reaction conditions in order to improve the enantioselectivity as well as the investigation of other chiral boranes. Overall, we have shown that it is possible to reduce carbonyls catalytically with a chiral

borane and using a stoichiometric silane as a hydride source, although the enantioselectivity of the process needs considerable optimization.

2.3 Chapter 2 References

1. Kolle, P.; Noth, H. The Chemistry of Borinium and Borenium Ions. Chemical Reviews 1985, 85, 399. 2. Piers, W. E.; Bourke, S. C.; Conroy, K. D. Borinium, Borenium, and Boronium Ions: Synthesis, Reactivity, and Applications. Angewandte Chemie International Edition 2005, 44, 5016.

3. Keske, E. C.; Zenkina, O. V.; Wang, R.; Crudden, C. M. Synthesis and Structure of Silver and Rhodium 1,2,3-Triazol-5-ylidene Mesoionic Carbene Complexes. Organometallics 2011, 31, 456. 4. Keske, E. C.; Zenkina, O. V.; Wang, R.; Crudden, C. M. Synthesis and Structure of Palladium 1,2,3-Triazol-5-ylidene Mesoionic Carbene PEPPSI Complexes and Their Catalytic Applications in the Mizoroki. Organometallics 2012, 31, 6215. 5. Keske, E. C. N-Heterocyclic and Mesoionic Carbene Complexes of Rhodium and Palladium: Coordination Chemistry and Catalysis; Queen's University: Kingston, Ontario, Canada, 2015; pp 138-183.

6. Mathew, P.; Neels, A.; Albrecht, M. 1,2,3-Triazolylidenes as Versatile Abnormal Carbene Ligands for Late Transition Metals. Journal of the American Chemical Society 2008, 13534. 7. Horn, M.; Mayr, H.; Lacote, E.; Merlin, E.; Deander, J.; Wells, S.; McFadden, T.; Curran, D. P. N-Heterocyclic Carbene Boranes are Good Hydride Donors. Organic Letters 2012, 14, 82. 8. Martin, D.; Melaimi, M.; Soleilhavoup, M.; Bertrand, G. A Brief Survey of Our Contribution to Stable Carbene Chemistry. Organometallics 2011, 30, 5304. 9. de Oliveira Freitas, L. B.; Eisenberger, P.; Crudden, C. M. Mesoionic Carbene−Boranes. Organometallics 2013, 32, 6635. 10. Farrell, J. M.; Posaratnanathan, R. T.; Stephan, D. W. A Family of N-heterocyclic Carbene- Stabilized Borenium Ions for Metal-Free Imine Hydrogenation Catalysis. Chemical Science 2015, 6, 2010.

11. Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C. M. Hydrogenations at Room Temperature and Atmospheric Pressure with Mesoionic Carbene-Stabilized Borenium Catalysts. Angewandte Chemie International Edition 2015, 2467, 54. 12. Erker, G.; Stephan, D. W. Topics in Current Chemistry; Springer: Berlin, German, 2013; Vol. 332, pp 196-198. 13. Liu, Y.; Du, H. Metal-Free Borane-Catalyzed Highly Stereoselective Hydrogenation of Pyridines. Journal of the American Chemical Society 2013, 135, 12968. 14. Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. Asymmetric Allyl- and Crotylboration with the Robust, Versatile, and Recyclable 10-TMS-9-borabicyclo[3.3.2]decanes. Journal of the American Chemical Society 2005, 127, 8044. 15. Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.; Medina, J. R.; Matos, K.; Soderquist, J. A. 9-Borabicyclo[3.3.2]decanes and the Asymmetric Hydroboration of 1,1- Disubstituted Alkenes. Journal of the American Chemical Society 2008, 130, 9218. 16. Jonnalagadda, S. C.; Suman, P.; Patel, A.; Jampana, G.; Colfer, A. Allylboration. In Boron Reagents in Synthesis; Coca, A., Ed.; American Chemical Society, 2016; pp 67 - 122. 17. Canales, E.; Prasad, K. G.; Soderquist, J. A. B-Allyl-10-Ph-9-borabicyclo[3.3.2]decanes: Strategically Designed for the Asymmetric Allylboration of Ketones. Journal of the American Chemical Society 2005, 127, 11572. 18. Munoz-Hernandez, L.; Soderquist, J. A. Asymmetric γ-Methoxyallylation with the Robust 10- TMS-9-Borabicyclo[3.3.2]decanes. Organic Letters 2009, 11, 2571. 19. Hernandez, E.; Soderquist, J. A. Nonracemic α-Allenyl Carbinols from Asymmetric Propargylation with the 10-Trimethylsilyl-9-borabicyclo[3.3.2]decanes. Organic Letters 2005, 7, 5397. 20. Lai, C.; Soderquist, J. A. Nonracemic Homopropargylic Alcohols via Asymmetric Allenylboration with the Robust and Versatile 10-TMS-9-borabicyclo[3.3.2]decanes. Organic Letters 2005, 7, 799.

21. Gonzalez, A. Z.; Soderquist, J. A. β-Silylated Homopropargylic Amines via the Asymmetric Allenylboration of Aldimines. Organic Letters 2007, 9, 1081. 22. Canales, E.; Hernandez, E.; Soderquist, J. A. Nonracemic 3°-Carbamines from the Asymmetric Allylboration of N-Trimethylsilyl Ketimines with B-Allyl-10-phenyl-9- borabicyclo[3.3.2]decanes. Journal of the American Chemical Society 2006, 128, 8712.

23. Masamune, S.; Kim, B. M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.; Imai, T. Organoboron Compounds in Organic Synthesis. 1. Asymmetric Hydroboration. Journal of the American Chemical Society 1985, 107, 4549. 24. Farrell, J. M.; Heiden, Z. M.; Stephan, D. W. Metal-Free Transfer Hydrogenation Catalysis by

B(C6F5)3. Organometallics 2011, 30, 4497. 25. Oestreich, M.; Chatterjee, I. B(C6F5)3-Catalyzed Transfer Hydrogenation of Imines and Related Heteroarenes Using Cyclohexa-1,4-dienes as a Dihydrogen Source. Angewandte Chemie International Edition 2015, 54, 1965.

26. Mayer, U.; Gutmann, V.; Gerger, W. The Acceptor Number - A Quantitative Empirical Parameter for the Electrophilic Properties of Solvents. Monatshefte fur Chemie 1975, 106, 1235. 27. Beckett, M. A.; Strickland, G. C. A Convenient N.M.R. Method for the Measurement of Lewis Acidity at Boron Centres: Correlation of Reaction Rates of Lewis Acid Initiated Epoxide Polymerizations with Lewis Acidity. Polymer 1996, 37, 4629. 28. Mewald, M.; Fröhlich, R.; Oestreich, M. An Axially Chiral, Electron-Deficient Borane: Synthesis, Coordination Chemistry, Lewis Acidity, and Reactivity. Chemistry a European Journal 2011, 17, 9406.

29. Clark, E. R.; Del Grosso, A.; Ingleson, M. J. The Hydride-Ion Affinity of Borenium Cations

and Their Propensity to Activate H2 in Frustrated Lewis Pairs. Chemistry a European Journal 2013, 19, 2462. 30. Parks, D. J.; Piers, W. E. Tris(pentafluorophenyl)boron-Catalyzed Hydrosilation of Aromatic Aldehydes, Ketones, and Esters. Journal of the American Chemical Society 1996, 118, 9440.

31. Parks, D. J.; Blackwell, J. M.; Piers, W. E. Studies on the Mechanism of B(C6F5)3-Catalyzed Hydrosilation of Carbonyl Functions. Journal of Organic Chemistry 2000, 65, 3090.

32. Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E. B(C6F5)3-Catalyzed Hydrosilation of Imines via Silyliminium Intermediates. Organic Letters 2000, 2, 3921.

33. Blackwell, J. M.; Morrison, D. J.; Piers, W. E. B(C6F5)3 Catalyzed Hydrosilation of Enones and Silyl Enol Ethers. Tetrahedron 2002, 58, 8247. 34. Chen, J.; Lalancette, R. A.; Jakle, F. Synthesis and Lewis Acid Properties of a Ferrocene- Based Planar-Chiral Borenium Cation. Chemical Communications 2013, 49, 4893.

35. Denmark, S. E.; Ueki, Y. Lewis Base Activation of Lewis Acids: Group 13. In Situ Generation and Reaction of Borenium Ions. Organometallics 2013, 32, 6631.

36. Rendler, S.; Oestreich, M. Conclusive Evidence for an SN2-Si Mechanism in the B(C6F5)3- Catalyzed Hydrosilylation of Carbonyl Compounds: Implications for the Related Hydrogenation. Angewandte Chemie International Edition 2008, 47, 5997.

37. Caputo, C. B.; Stephan, D. W. Activation of Alkyl C–F Bonds by B(C6F5)3: Stoichiometric and Catalytic Transformations. Organometallics 2012, 31, 27.

38. Porwal, D.; Oestreich, M. B(C6F5)3-Catalyzed Reduction of Aromatic and Aliphatic Nitro Groups with Hydrosilanes. European Journal of Organic Chemistry 2016, 2016, 3307. 39. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: New York, 2007. 40. Gandhamsetty, N.; Joung, S.; Park, S. W.; Park, S.; Chang, S. Boron-Catalyzed Silylative Reduction of Quinolines: Selective sp3 C−Si Bond Formation. Journal of the American Chemical Society 2014, 136, 16780. 41. Manas, M. G.; Sharninghausen, L. S.; Balcells, D.; Crabtree, R. H. Experimental and Computational Studies of Borohydride Catalyzed Hydrosilylation of a Variety of C=O and C=N Functionalities Including Esters, Amides and Heteroarenes. New Journal of Chemistry 2014, 38, 1694. 42. Heiden, Z. M.; Lethem, A. P. Establishing the Hydride Donor Abilities of Main Group Hydrides. Organometallics 2014, 34, 1818. 43. Hansch, C.; Leo, A.; Taft, R. W. A Survey of Hammett Substituent Constants and Resonance and Field Parameters. Chemical Reviews 1991, 91, 165. 44. Canseco-Gonzalez, D.; Petronilho, A.; Mueller-Bunz, H.; Ohmatsu, K.; Ooi, T.; Albrecht, M. Carbene Transfer from Triazolylidene Gold Complexes as a Potent Strategy for Inducing High Catalytic Activity. Journal of the American Chemical Society 2013, 135, 13193. 45. Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.; Medina, J. R.; Metos, K.; Soderquist, J. A. 9-Borabicyclo[3.3.2]decanes and the Asymmetric Hydroboration of 1,1- Disubstituted Alkenes. Journal of the American Chemical Society 2008, 130, 9218. 46. Fan, C.; Mercier, L. G.; Piers, W. E.; Tuononen, H. M.; Parvez, M. Dihydrogen Activation by Antiaromatic Pentaarylboroles. Journal of the American Chemical Society 2010, 132, 9604.

Chapter 3

Future Work and Conclusion

3.1 Future Work

Due to the disappointing results observed in the synthesis of 9-BBD based-borenium ion catalysts, we decided to look into other chiral boranes such as the previously mentioned Masamune boranes with the aim of developing an enantioselective borenium ion catalysts. Also worth investigating are chiral counter ions to use in conjunction with our borenium ion catalysts. This is currently under investigation by fellow Crudden group member Joshua Clarke. Furthermore, the development of an enantioselective borenium ion catalyst would be highly desirable in its application to our borenium ion catalyzed hydrosilylation chemistry.

Figure 3-1 Proposed MIC-stabilized Masamune borenium ion

The borenium ion-catalyzed hydrosilylation proved to be highly versatile. This invokes the question of whether or not other bonds may be activated by our borenium ion catalyst, most obviously B–H bonds. This seems highly probable as previously in our group we showed that

DABCO (1,4-diazabicyclo[2.2.2]octane) stabilized borenium ions generated from H–Bpin could catalyze the hydroboration of imines. (1) Other substrates that may be of interest include α-diazo esters which have recently been shown to be activated by BCF, allowing for the selective ortho- substitution of phenols. (2) Additionally, mechanistic investigations would be helpful to show if the borenium ion-catalyzed hydrosilylation of imines proceeds via the formation of a σ-complex between the Si–H bond and the borenium ion, or if the hydrosilylation proceeds via some other

mode of silane activation. This could be achieved by developing a Hammett plot for the reaction as well as investigated the stereochemical outcome of a silane when using a chiral at silicon silane such as was done by Oestrich. (3)

Lastly the BBD borohydride-catalyzed hydrosilylation of carbonyl compounds still holds promise. Further screening of reaction conditions is warranted in order to increase the enantioselectivity of the reaction. Furthermore, other chiral boranes developed for producing chiral borenium ions would be worth investigating in this catalytic manifold, to see if any improvement over the BBDs could be achieved.

3.2 Conclusions

We began this research with the aim to further broaden the field of borenium ion catalysis,

specifically towards dihydrogen activation. Towards this goal, we developed catalysts capable

of the room temperature hydrogenation of imines and N-heterocycles at ambient and near

ambient pressures. (4) We further developed this reaction, synthesizing chiral derivatives of

our catalyst, such as 2-21a. Unfortunately, these studies were less successful with the catalysts

either proving to be unstable, as was observed in the case of the BBDs, or only achieving low

levels of enantioselectivity when using a chiral carbene ligand, as was observed by others. (5)

The disappointing enantioselectivities observed when using a chiral borenium ion catalyst

prompted us to investigate if hydride abstraction and re-addition by our catalyst could account

for the poor enantioselectivities observed. (5) NMR studies using borenium ion 2-3a revealed

that hydride abstraction from sp3 C–Hs alpha to nitrogen on bis[(R)-1-phenylethyl]amine was

indeed possible, however this only proceeded at significant rates at elevated temperatures. We

were thus able to conclude that hydride abstraction was unlikely responsible for any poor

enantioselectivity observed when using our borenium ion catalyst and that it should still be

possible to develop an enantioselective borenium ion catalyst.

Finally, in terms of borenium ion catalysis, we were able to show that not only are these

species especially active hydrogenating catalysts but are also very active hydrosilylation

catalysts, able to reduce both imines and N-heterocycles and tolerate various functionalities.

Lastly, we showed that we could use a chiral borohydride, specifically a 9-BBD,

catalytically for the hydrosilylation of carbonyl compounds. Unfortunately, the

enantioselectivities of these reactions were rather poor, however the investigations described

herein are nowhere near exhaustive and further exploration of this reaction is still warranted.

3.3 Chapter 3 References

1. Eisenberger, P.; Bailey, A. M.; Crudden, C. M. Taking the F out of FLP: Simple Lewis Acid−Base Pairs for Mild Reductions with Neutral Boranes via Borenium Ion Catalysis. Journal of the American Chemical Society 2012, 134, 17384.

2. Yu, Z.; Li, Y.; Shi, J.; Ma, B.; Liu, L.; Zhang, J. (C6F5)3B Catalyzed Chemoselective and ortho- Selective Substitution of Phenols with α-Aryl α-Diazoesters. Angewandte Chemie International Edition 2016, 55, 14807.

3. Rendler, S.; Oestreich, M. Conclusive Evidence for an SN2-Si Mechanism in the B(C6F5)3- Catalyzed Hydrosilylation of Carbonyl Compounds: Implications for the Related Hydrogenation. Angewandte Chemie International Edition 2008, 47, 5997. 4. Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C. M. Hydrogenations at Room Temperature and Atmospheric Pressure with Mesoionic Carbene-Stabilized Borenium Catalysts. Angewandte Chemie International Edition 2015, 2467, 54. 5. Lam, J.; Günther, B. A. R.; Farrell, J. M.; Eisenberger, P.; Bestvater, B. P.; Newman, P. D.; Melen, R. L.; Crudden, C. M.; Stephan, D. W. Chiral Carbene–Borane Adducts: Precursors for Borenium Catalysts for Asymmetric FLP Hydrogenations. Dalton Transaction 2016, 45, 15503. 6. Rendler, S.; Oestreich, M. Hypervalent Silicon as a Reactive Site in Selective Bond-Forming Processes. Synthesis 2005, 11, 1727.

Chapter 4

Experimental

4.1 General Experimental Considerations

Unless otherwise specified all reactions were conducted in oven dried (160 °C) glassware with magnetic stirring using Schlenk-line techniques under an atmosphere of dry argon or in an M.

Braun glovebox under an atmosphere of nitrogen with oxygen and water levels <15 ppm. Reactions conducted on NMR tube scale were carried out in either Teflon cap sealed or J. Young NMR tubes

(ø 5 mm). Toluene and THF were purified by passage through an activated aluminium oxide column, followed by distillation from sodium-benzophenone ketal. Hexanes and pentanes were distilled from sodium-benzophenone ketal. Dichloromethane, [D2]-dichloromethane, 1,2- dichloroethane, [D6]-benzene and α,α,α-trifluorotoluene were purified by mixing over CaH2 for at least 24 h followed by distillation. All solvents were degassed after purification by three cycles of freeze-pump-thaw and were stored over 4 Å molecular sieves for use in a glovebox. Solvents for chromatography were of at least ACS reagent grade and were used as received from commercial sources. Solvents for routine NMR spectroscopy were used as received. Silica gel 60 (particle size

0.040 - 0.063 mm, 230 – 400 mesh) purchased from Silicycle was used to purify indicated compounds by column chromatography. TLCs were run on silica gel coated aluminum plates with

UV indicator (F254) obtained by EMD Chemicals, Inc. and analyzed by UV/VIS and stained using a cerium ammonium molybdate or KMnO4 solution.

4.2 Reagents and Materials

9-Borabicyclo[3.3.1]nonane dimer, sodium bis(trimethylsilyl)amide (NaHMDS), sodium hydride, and lithium aluminium hydride powder were purchased from Aldrich, stored in a nitrogen filled glovebox, and used as received. 1 M 9-methoxy-9-borabicyclo[3.3.1]nonane in hexanes, polymethyhydrosiloxane and (1S,2S)-(+)-pseudoephedrine-HCl salt were purchased from Aldrich

and used as received. 2,6-Lutidine, 8-methyl quinoline, phenanthroline, fenchone, iodomethane, bis[(R)-1-phenylethyl]amine, tris(pentafluorophenyl)-borane, N-benzylidenebenzenesulfonamide

(2-6n), benzonitrile, benzophenone, p-bromoacetophenone, N,N-diethylbenzamide, 2- naphthaldehyde, dicyclohexyl ketone, methyl cinnamate, 4-tert-butylcyclohexanone, triethylsilane, phenyldimethylsilane, diethylsilane, diphenylsilane, and phenyl silane were purchased from

Aldrich and either distilled from CaH2 or sublimed prior to use. TMS-diazomethane was purchased

+ - from Acros chemicals and used as received. Ph3C B(C6F5)4 , was purchased from Strem stored in a nitrogen filled glovebox and used as received or synthesized as reported in the literature. (1)

Hydrogen gas was supplied by Praxair (5.0 purity) and used as received. The following compounds were synthesized as reported in the literature: sodium dihydrido-9-borata-[3.3.0]bicyclononane,

(209) phenyldiazomethane, (3) N-methylpseudoephedrine, (211) 1,3-diphenyl-1H-1,2,3-triazolium tetrafluoroborate, (5) and 1,3-dimethylimidazolium iodide. (6) Aldimines 2-5a, 2-5e, 2-5h–m,

(213) and ketamines 2-5b–d, 2-5f, 2-3g, 2-5o (8) were synthesized by literature procedures and were purified by either kugelrohr distillation or sublimation. MIC-boranes 2-1a-e, NHC-boranes

2-2a-c, and functionalized quinolines/pyridines (2-9a – h and 2-9 j – k) were synthesized as previously reported. (5). MIC-borane 2-1f was synthesized as reported in the literature. (9)

4.3 Characterization

NMR spectra were recorded on Bruker Avance 300 (1H: 300.13 13C: 75.47; QXI probe), Bruker

Avance 400 (1H: 400.13, 11B: 128.38, 13C: 100.62; BBI, BBFO and QNP probes), Bruker Avance

500 (1H: 500.19, 11B: 160.27, 13C: 125.62; BBI and BBFO probes), or Bruker Avance 600 (1H:

600.17, 11B: 192.56, 13C: 150.93; TBI probe) instruments operating at the denoted spectrometer frequency given in mega Hertz (MHz) for the specified nucleus. Samples were measured as solutions in the stated solvent at ambient temperature in non-spinning mode if not mentioned otherwise. Shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard for 1H and 13C NMR spectra and calibrated against the solvent residual peak.

11 19 (10) B signals are calibrated against external BF3·OEt2 and F against CFCl3. The following abbreviations are used to specify signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, qu = quintet, sept = septet, oct = octet, and m = multiplet; br. indicates a broad resonance. Coupling constants (J) are given in Hertz (Hz). GC-MS measurements were performed on an Agilent

Technologies GC 6850N/ MS 5975N VL MSD equipped with an Agilent Technologies HP-5MS column (length: 30 m, 0.25 mm inner diameter, 0.25 μm coating thickness) coupled to a quadrupole mass filter. Helium was used as the carrier gas with a constant flow of 1.2 mL/min. Separation of the injected species was achieved using the denoted temperature program and retention times tR are given in minutes (min). High resolution mass-spectra (HRMS) were measured by the Queen's Mass

Spectrometry and Proteomics Unit (MSPU) at Queen's University, Kingston, Ontario, Canada.

Mass spectra were measured on Applied Biosystems/MDS Sciex QStar XL QqTOF or Waters ZQ

Single Quad. Fragment signals are given in mass per charge number (m/z). Enantiopurity was obtained by SFC (supercritical fluid chromatography) from a JASCO Instruments SFC HPLC equipped with HPLC columns (CHIRALPAK IA, IB, IC, ID, IE, IF: length 250 mm, 4.6 mm, particle size 5 μm), operating at the stated flow-rate and pressure of supercritical CO2 with the indicated amount of admixed modifier solvent. Retention times (tR) are given in minutes (min).

22 Optical rotations [α] D were measured on a Perkin-Elmer 241MC polarimeter as solutions in dichloromethane at concentration of 0.045 g mL–1 at 22 °C at 589 nm in a 0.5 dm cell, and given as specific rotations (° cm2 g–1).

4.4 Synthesis

4.4.1 General Procedure for Hydrogenation using MIC-Borenium in an Autoclave (GP1)

+ - In a nitrogen filled glovebox, a one dram vial was charged with MIC-borane and Ph3C B(C6F5)4 .

+ - A stir bar was then added to the vial containing MIC-borane and Ph3C B(C6F5)4 along with CH2Cl2 by syringe, the mixture was then stirred for 1 – 2 min until the solution became homogenous and decolorized. The substrate was then added, either by μL-pipette in the case of liquids or in the case 97

for solids weighed out in a separate 1 dram and transferred by glass pipette after dissolving in the reaction solvent followed by washing. The vial was then placed in a 50 mL Parr-bomb, the bomb sealed, and the aperture was covered with a septum. The bomb was then removed from the glovebox and the septum was quickly replaced by a pressure gage. The bomb was charged with hydrogen gas by first purging the hose, followed by repeatedly (5 x) loading to the indicated pressure of gas into the vessel. The reaction was stirred at 1200 rpm at ambient temperature for 19 h. After the indicated time, the Parr-bomb was opened, the reaction was transferred to a secondary flask and diluted with CHCl3. An internal standard in a solution of CHCl3 was added and the solution was mixed well by pipette. An aliquot, ~1mL, was then removed, the solvent removed by rotary- evaporation and the remaining residue re-dissolved in CDCl3 (0.6 mL). The sample was then analyzed by 1H NMR to determine yields. In all cases 2-5b–g the 1H NMR spectra matched previously reported literature reports. (11) (12) (13) (14) In the case of reactions run under 5 atm of dihydrogen, a carefully calibrated gauge was used to pressurize the Parr-bomb.

4.4.2 Fenchone Competition Experiment

(Eq.4-6)

In a nitrogen filled glovebox, a one dram vial was charged with MIC-borane 2-1a (8.8 mg, 0.026

+ - mmol) and Ph3C B(C6F5)4 (23.3 mg, 0.025 mmol). A stir bar was then added to the MIC-borane

+ - and Ph3C B(C6F5)4 along with CH2Cl2 by syringe, the mixture was then stirred for 1 – 2 min until the solution became homogenous and decolorized. 2-5b (48.3 mg,0.24 mmol) and fenchone (38.5 mg, 0.25 mmol) was then weighed out in a separate 1 dram and transferred by glass pipette after dissolving in CH2Cl2 followed by washing. The reaction was done in 0.25 mL CH2Cl2 total volume.

The vial was then placed in a 50 mL Parr-bomb, the bomb sealed, and the aperture was covered

with a septum. The bomb was then removed from the glovebox and the septum was quickly replaced by a pressure gage. The bomb was charged with hydrogen gas by first purging the hose, followed by repeatedly (5 x) loading to the indicated pressure of gas into the vessel. The reaction was stirred at 1200 rpm at ambient temperature for 18 h. After the indicated time, the reaction mixture was transferred to a 50 mL round-bottom flask, diluted with CHCl3, an internal standard was then added (0.2 mL 0.067g/mL 1,3,5-trimethoxy benzene in CHCl3) and the solution was mixed thoroughly. An aliquot, ~1 mL, was then removed and the solvent removed by rotary evaporation. The remaining residue was then dissolved in CDCl3 and the yield was determined by

1H NMR.

8-methyl-1,2,3,4-tetrahydroquinoline. Synthesized following GP1 from 2-1a

+ - (8.65 mg, 25.1 μmol), Ph3C B(C6F5)4 (24.1 mg, 26.1 μmol), and 8-methylquinoline

(2-9g, 36.4 mg, 0.254 mmol) in CH2Cl2 (0.25 mL) under 5 atm of H2 at ambient

temperature for 18 h. The title compound was isolated after flash column chromatography (silica gel 60, hexanes/EtOAc 20:1) as a lightly yellow, viscous oil. Yield: 32 mg

1 (0.171 mmol, 87%). H NMR (CDCl3, 400 MHz) δ 1.99 (m, 2H), 2.13 (s, 3H), 2.84 (t, J = 6.4 Hz,

13 2H), 3.44 (m, 2H), 3.68 (br. s, 1H), 6.59 (t, J = 6.6 Hz,1H), 6.91 (m, 2H); C NMR (CDCl3, 100

MHz) δ 17.3, 22.3, 27.4, 42.5, 116.5, 121.0, 121.3, 127.5, 128.0, 142.8; HRMS(ESI-TOF): m/z calc. 148.1121 ([M + H]+), found 148.1148 ([M + H]+).

1,2,3,4-tetrahydro-1,10-phenanthroline. Synthesized following GP1 from 2-

+ - 1a (8.9 mg, 25.9 μmol), Ph3C B(C6F5)4 (23.9 mg, 25.9 μmol), and 9,10-

phenanthroline (2-9h, 45.2 mg, 0.251 mmol) in CH2Cl2 (0.25 mL) under 102 atm

of H2 at ambient temperature for 18 h. The title compound was isolated after flash column chromatography (silica gel 60, hexanes/EtOAc 20:1) resulting in a viscous yellow oil.

1 Yield: 22.0 mg (0.119 mmol, 47%). H NMR (CDCl3, 400 MHz) δ 2.09 (m, 2H), 2.94 (t, J = 6.3

Hz, 2H), 3.55 (m, 2H), 5.96 (br. s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.31 (

13 m, 1H), 8.04 (d, J = 7.6 Hz, 1H) 8.71 (m, 1H.); C NMR (CDCl3, 100 MHz) δ 22.0, 27.2, 41.4,

113.2, 116.7, 120.7, 127.5, 129.2, 136.0, 137.6, 140.8, 147.1.

2,6-Dimethylpiperidine. Synthesized following GP1 from 2-1a (8.7 mg, 25.3

+ - μmol), Ph3C B(C6F5)4 (24.3 mg, 26.3 μmol), and 2,6-lutidine (2-9i, 29.7 mg,

0.27 mmol) in CH2Cl2 (0.25 mL) under 102 atm of H2 at ambient temperature for 24 h. Yield (28%) was determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. The obtained NMR spectra matched previously reported literature data. (15)

2-Methyl-6-Phenylpiperidine. Synthesized following GP1 from 2-1a (8.8 mg,

+ - 25.6 μmol), Ph3C B(C6F5)4 (22.9 mg, 24.8 μmol), and 2-methyl-6-

phenylpyridine (2-6j, 43.4 mg, 0.256 mmol) in CH2Cl2 (0.25 mL) under 102 atm

1 of H2 at ambient temperature for 24 h. Yield (33%) was determined by H NMR spectroscopy using

1,3,5-trimethoxybenzene as an internal standard. The obtained NMR spectra matched previously reported literature data. (220)

2,6-Diphenylpiperidine. Synthesized following GP1 from 2-1a (8.9 mg, 25.9

μmol),

+ - Ph3C B(C6F5)4 (23.1 mg, 25.0 μmol), and 2,6-diphenylpyridine 2-6j j, 59.4 mg,

0.25 mmol) in CH2Cl2 (0.25 mL) under 102 atm of H2 at ambient temperature for 48 h. Yield (55%) was determined by 1H NMR spectroscopy using ferrocene as an internal standard. The obtained

NMR spectra matched previously reported literature data. (17)

(rac) – B-Methoxy-10-phenyl-9-borabicyclo[3.3.2]decane. Prepared

according to the procedure by Soderquist and co-workers. (18) A 100 mL Schlenk

flask equipped with a stir bar and rubber septum was charged with 39 mL of 1M

100

B-MeO-9BBN (2-14 39 mmol) in hexane and cooled to 0 °C in an ice-water bath.

Phenyldiazomethane (39 mmol), prepared according to literature procedure (3), as a 1M solution in hexanes was then added by syringe drop-wise while stirring. The mixture was then left to warm to room temperature for 16 h. The solvent was then removed in vacuo leaving a viscous yellow oil.

The yellow oil was then distilled under vacuum at 140 °C to afford (rac) – 2-16a as clear yellow oil in 44 % yield (4.174 g). Note unreacted 1M B-MeO-9BBD elutes first in the range of 40 – 80

1 °C. H NMR (499 MHz, C6D6) δ 7.30 – 7.24 (m, 2H), 7.17 (m, 3H), 3.32 (s, 3H), 2.54 (s 1H), 2.37

13 (s 1H), 2.01 – 1.32 (m, 13H). C NMR (126 MHz, C6D6) δ 145.34, 130.88, 128.92, 128.64, 125.38,

11 53.58, 43.49, 39.40, 29.57, 28.57, 27.64, 26.99, 24.86, 22.12. B NMR (160 MHz, C6D6) δ 54.37.

(rac) – B-Methoxy-10-trimethylsilyl-9-borabicyclo[3.3.2]decane. Prepared

according to the procedure by Soderquist and co-workers. (18) A two neck 50

mL round-bottom flask under argon fitted with a magnetic stir bar, condenser and septum was charged with 10 mL of a 1 M solution of B-MeO-9BBN (2-14 10 mmol) in hexanes and 5.5 mL of a 2 M solution of TMS-diazomethane (11 mmol) in hexanes. The mixture was then refluxed for 18 h. After the indicated time the reaction was cooled to room temperature and the solvent was removed in vacuo leaving a viscous yellow oil. The yellow oil was then distilled under vacuum at 80 °C to afford (rac) – 2-16b as clear oil in 91 % yield (2.185 g). 1H NMR (400 MHz,

CDCl3) δ 3.65 (s, 3H), 2.26 (s, 1H), 1.85 – 1.76 (m, 2H), 1.70 – 1.29 (m, 1H), 0.59 (s, 1H), 0.05 (s,

13 9H). C NMR (101 MHz, CDCl3) δ 52.93, 33.46, 32.98, 31.77, 27.83, 25.64, 24.71, 22.06, 0.95.

11 B NMR (128 MHz, CDCl3) δ 54.94.

(+) – (1S,2S-N-Methylpseudoephedrinyl)-(10S)-phenyl-

9borabicyclo[3.3.2]decane. Prepared according to the procedure by

Soderquist and co-workers. (19) In a nitrogen filled glovebox, a 2-neck 50 mL

round-bottom flask was charged charged with 12.5 mmol (3.0251g) of B-

101

methoxy-10-phenyl-9-borabicyclo [3.3.2]decane (rac) – 2-16a and 6.25 mmol (1.1276g) (1S,2S)–

N-methylpsudoephedrin, then fitted with a megnetric stir bar and two spetums. The flask was then brought out of the glovebox, fitted with a condenser, attached to a Schlenk line and placed under argon. Hexanes (13.5 mL) was then added by syringe and the solution was refluxed for 6 h. The solution was then left to cool to room temperature resulting in the formation of white, needle-like crystals. The mother liquor was then removed by syringe and the crystals were washed (3 x) with hexanes. The crystals were dried under vacuum, collected and stored in a nitrogen filled glovebox,

1 giving (S) – 2-18a in 21 % yield (42% of S enantiomer, 1.025 g). H NMR (400 MHz, CDCl3) δ

7.56 (d, J = 7.6 Hz, 2H), 7.40 – 7.26 (m, 5H), 7.20 (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 4.21

(d, J = 9.7 Hz, 1H), 2.90 (dt, J = 13.3, 6.8 Hz, 1H), 2.40 – 2.31 (m, 7H), 2.03 (t, J = 8.2 Hz, 1H),

1.97 – 1.45 (m, 11H), 1.33 (p, J = 6.7, 6.3 Hz, 1H), 1.20 (t, J = 7.8 Hz, 1H), 0.75 (d, J = 6.7 Hz,

13 3H). C NMR (101 MHz, CDCl3) δ 131.01, 128.42, 127.85, 127.76, 127.51, 123.62, 81.15, 67.82,

11 42.74, 41.39, 32.11, 31.24, 29.81, 29.30, 24.85, 22.24, 7.88. B NMR (128 MHz, CDCl3) δ 55.10,

D 18.23. [a] 23 = + 77° (c = 0.045 g/mL in CH2Cl2).

(rac) – Lithium-B-H2-phenyl-9-borabicyclo[3.3.2]decane. In a nitrogen

filled glovebox, a 4 dram vial fitted with a stir bar was charged with 0.5 mmols

(0.12243 g) (rac) – B-Methoxy-10-trimethylsilyl-9-borabicyclo[3.3.2]decane

(2-16a), and 3 mL THF. While string 0.5 mmols (0.01946) powdered LiAlH4 was added portion-wise, the solution was then left to stir for 16 hr. The reaction mixture was filtered through a plug of celite, and the solvent removed in vacuo, resulting in (rac) – 2-19a (0.092 g) as white powder. 2-19a always formed as an adduct with 2 molecules of THF by 1H NMR. 1H NMR

(400 MHz, C6D6) δ 7.68 (d, J = 7.6 Hz, 2H), 7.25 (t, J = 7.4 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 3.31

– 3.12 (THF, m, 8H), 2.98 (s, 1H), 2.73 (s, 1H), 2.47 – 1.45 (m, 12H), 1.27 – 1.14 (THF, m, 8H).

13 C NMR (126 MHz, C6D6) δ 159.52, 129.66, 127.41, 122.19, 67.93 (THF), 43.96 – 42.69 (m),

38.49, 34.80, 33.76, 31.42, 26.99 (q, J = 90.1, 42.0 Hz), 26.01, 25.09 (THF), 24.21, 22.45, 14.00.

102

4.4.3 General Procedure for the Synthesis of Carbene-BBDs, Room Temperature (GP2) In a nitrogen filled glovebox, a 4 dram vial, equipped with a stir bar, was charged with lithium-B-

H2-phenyl-9-borabicyclo[3.3.2]decane (2-19a) and THF. Once 2-19a had dissolved, MeI was added by syringe while stirring and the solution was mixed for 1 h. The gradual generation of bubbles was observed and the solution turned opaque and white in colour. The solution was then filtered through a plug of celite® and concentrated to dryness in vacuo. Carbene precursor was then added (2-20 or 2-22) to the remaining solid and the mixture was dissolved in THF. Base, as a solution in THF, was then added dropwise to the reaction mixture followed by stirring at room temperature for 16 h. The solution was then filtered through a plug of celite® and the solvent was removed in vacuo. The crude reaction mixture was then analyzed by 1H NMR and the final product was recrystallized at - 25 °C.

4.4.4 General Procedure for the Synthesis of Carbene-BBDs, -78 °C (GP3) In a nitrogen filled glovebox, a 4 dram vial equipped with a stir bar, was charged with Lithium-B-

H2-phenyl-9-borabicyclo[3.3.2]decane (2-19a) and THF. Once 2-19a had dissolved, MeI was added by syringe while stirring and the solution was left to mix for 1 h. The gradual generation of bubbles was observed and the solution turned opaque and white in colour. The solution was then filtered through a plug of celite® into a Schlenk flask, equipped with a stirbar, and concentrated to dryness in vacuo. Carbene precursor (2-20 or 2-22) was then added to the remaining solid and the mixture was dissolved in the indicated solvent. The Schlenk flask was then sealed with a septum, brought out of the glovebox, attached to a Schlenk line, placed under argon, and cool to -78 °C.

Base, as a 1 M solution in the reaction solvent, was then added dropwise to the reaction mixture while stirring at -78 °C. The mixture was then stirred for 16 h and allowed to warm room temperature over the indicated time. The Schlenk flask was brought back into the glovebox, the solution was filtered through a plug of celite® and concentrated in vacuo. The crude reaction mixture was then analyzed by 1H NMR and the final product was recrystallized at - 25 °C.

103

(rac) – 9-(1,3-diphenyl-1,2,3-triazol-5-ylidene)-B–H-(10)-phenyl-9-

borabicyclo [3.3.2 ]decane. Was synthesized according to GP2. In a

nitrogen filled glovebox, a 4 dram vial equipped with a stir bar, was charged

with 0.25 mmol (0.061 g) (rac) – Lithium-B-H2-phenyl-9- borabicyclo[3.3.2]decane (2-19a) and 2 mL THF and stirred. Once 2-16a dissolved, 0.5 mmol (0.03 mL) MeI was added by syringe and stirred for 1 h. The gradual generation of bubbles was observed and the solution turned opaque and white in colour. The solution was filtered through a plug of celite® and concentrated to dryness in vacuo. 0.25 mmol (0.04590 g) Ph2MICBF4 (2-20) was added to the remaining residue, and the mixture was dissolved in 4 mL THF. 0.25 mmol (0.07727)

NaHMDS dissolved in 1 mL THF was then added dropwise to the mixture while stirring. The mixture was stirred for 16 h at room temperature and then concentrated in vacuo and recrystallized from toluene/pentanes at – 25 °C affording (rac) – 2-21a in 14 % yield (0.0149g). 1H NMR (600

MHz, C6D6) δ 7.90 (s, 1H), 7.76 (d, J = 7.1 Hz, 2H), 7.45 – 7.37 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H),

7.10 (t, J = 7.3 Hz, 1H), 7.00 – 6.94 (m, 2H), 6.89 – 6.82 (m, 3H), 6.78 (t, J = 7.9 Hz, 2H), 2.82 (s,

1H), 2.66 – 2.55 (m, 2H), 2.38 – 2.04 (m, 10H), 1.95 (dt, J = 10.9, 3.6 Hz, 1H), 1.53 – 1.42 (m,

13 1H). C NMR (126 MHz, C6D6) δ 157.19, 137.71, 135.06, 130.07, 129.85, 129.48, 129.41, 128.48,

127.01, 125.86, 123.16, 120.67, 43.92, 37.50, 35.94, 32.19, 30.63, 25.78, 25.06. 11B NMR (128

MHz, C6D6) δ -15.03 (d, J = 86.5 Hz).

4.4.5 BCF Racemization Experiment In a nitrogen filled glovebox, a J-Young NMR tube was charged with 0.06 mmol (0.0306g) tris(pentafluorophenyl)borane, 0.5 mL CD2Cl2, and 0.6 mmol (140 μL) bis[(R)-1- phenylethyl]amine, added by μL pipette. Upon addition of bis[(R)-1-phenylethyl]amine the J-

Young tube was quickly sealed, brought out of the glovebox and analyzed periodically by 1H NMR.

For heating the J-Young tube was placed in an oil bath up to the solvent level for the time specified

104

Figure 4-1 BCF catalyzed racemization of 2-25 followed by 1H NMR

4.4.6 MIC-Borenium Racemization Experiment In a nitrogen filled glovebox, a 1 dram vial was charged with 0.06 mmol (0.0202 g) MIC-borane

+ - 2-1a and 0.06 mmol (0.0553g) Ph3C B(C6F5)4 , a stir bar was then added along with 0.2 mL CD2Cl2.

The mixture was then stirred for 1 – 2 min until the solution became homogenous and decolorized.

The solution was then transfer to a J-Young NMR with washing (3 x with 0.1 mL CD2Cl2). 0.6 mmol (140 μL) bis[(R)-1-phenylethyl]amine was added by μL pipette to the borenium solution and the J-Young tube was quickly sealed, brought out of the glovebox and analyzed periodically by 1H

NMR. For heating the J-Young tube was placed in an oil bath up to the solvent level for the time specified

105

Figure 4-2 MIC-boreniun catalyzed racemization of 2-25 followed by 1H NMR

4.4.7 General Procedure for the MIC-Borenium Catalyzed Hydrosilylation of Imines (GP4) In a nitrogen filled glovebox, a one dram vial was charged with MIC-borane, 2-1a, and

+ - Ph3C B(C6F5)4 . After adding a stir bar, the indicated solvent was added by syringe. The mixture was then stirred for 1 – 2 min until the solution became homogenous and decolorized. The solution was then transfer to a J-Young NMR tube by glass pipette with washing (3x). The substrate was either added as a solution in the case of solids or neat in the case of liquids by μL pipette. The indicated silane was then added by μL pipette and the J-Young tube was sealed, brought out of the glovebox and the reaction monitored by 1H NMR. When the reaction had reached completion after the indicated time, the contents of the J-Young tube were then transferred to a 4 dram vial fitted with a stirbar. While stirring 2 mL of a 1:1 MeOH/2 M KOH was added dropwise by glass pipette, and the solution was left to stir for 1 h. The solution was then diluted with 5 mL H2O and the 106

solution extracted with 10 ml CH2Cl2 (3 x). The final solution was concentrated in vacuo and purified by silica gel column chromatography.

4-Methyl-N-phenylbenzylamine. Synthesized following GP4 from from 2-

+ - 1a (10.59 mg, 5 μmol), Ph3C B(C6F5)4 (23 mg, 5 μmol), 2-5h (98.38 mg, 0.5

mmol), and phenylsilane (88 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) at ambient temperature for 21.5 h. The title compound was isolated after flash column chromatography (silica

1 gel 60 hexanes/Et3N 48:1, Rf = 0.26) as a clear oil. Yield 71 % (71 mg, 0.359 mmol) H NMR (400

MHz, CDCl3) δ 6.91 (d, J = 7.8 Hz, 2H), 6.87 – 6.76 (m, 4H), 6.37 (t, J = 7.3 Hz, 1H), 6.28 (d, J =

13 7.8 Hz, 2H), 3.92 (s, 2H), 3.59 (s, 1H), 2.00 (s, 3H). C NMR (126 MHz, CDCl3) δ 148.32, 136.92,

136.47, 129.39, 129.33, 127.60, 117.56, 112.92, 112.91, 48.15, 21.21.

4-Methoxy-N-phenylbenzylamine. Synthesized following GP4 from from

+ - 2-1a 1.0 mg, 2.5 μmol), Ph3C B(C6F5)4 (2.3 mg, 2.5 μmol), 2-5i (52.8 mg,

0.25 mmol) and phenylsilane (34 μL, 0.275 mmol) in CH2Cl2 (0.5 mL) at

ambient temperature for 1 h. The title compound was isolated after flash column chromatography (silica gel 60 hexanes/Et3N 10:1) as an ocher solid. Yield 96 % (51 mg,

1 0.239 mmol). H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.6 Hz, 2H), 7.25 – 7.19 (m, 2H), 6.92

(td, 2H), 6.76 (tt, J = 7.3, 1.1 Hz, 1H), 6.70 – 6.62 (m, 2H), 4.29 (s, 2H), 3.98 (s, 1H), 3.84 (s, 3H).

13 C NMR (101 MHz, CDCl3) δ 158.98, 148.33, 131.55, 129.34, 128.89, 117.59, 114.14, 112.95,

55.38, 47.90.

4-Trifluoromethyl-N-phenylbenzylamine. Synthesized following GP4

+ - from from 2-1a (5.6 mg, 12.5 μmol), Ph3C B(C6F5)4 (11.5 mg, 12.5 μmol),

2-5j (64.1 mg, 0.25 mmol) and phenylsilane (43 μL, 0.275 mmol) in CH2Cl2

(0.5 mL) at ambient temperature for < 5 min. The title compound was isolated after flash column chromatography (silica gel 60 hexanes/Et2O/Et3N 46:5:1, Rf = 0.18) as

107

1 clear oil. Yield 71 % (46 mg 0.183 mmol). H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.1 Hz, 2H),

7.51 (d, J = 7.8 Hz, 1H), 7.26 – 7.16 (m, 2H), 6.77 (tt, J = 7.3, 1.1 Hz, 1H), 6.64 (dt, J = 7.7, 1.1

13 Hz, 2H), 4.43 (s, 2H), 4.15 (s, 1H). C NMR (101 MHz, CDCl3) δ 147.81, 143.91, 143.90, 129.74,

129.47, 127.56, 125.73, 125.70, 125.66, 125.62, 122.99, 118.09, 113.03, 47.91. 19F NMR (376

MHz, CDCl3) δ -63.01.

3-Nitro-N-phenylbenzylamine. Synthesized following GP4 from from 2-

+ - 1a (1.1 mg, 2.5 μmol), Ph3C B(C6F5)4 (2.4 mg, 2.5 μmol), 2-5k (56.8 mg,

0.25 mmol) and phenylsilane (34 μL, 0.275 mmol) in CH2Cl2 (0.5 mL) at 65

°C for 72 h. The title compound was isolated after flash column chromatography (silica gel 60 hexanes/Et2O/Et3N 24:25:1, Rf = 0.31) and recrystallized from hot hexanes as fine orange needle

1 crystals. Yield 82 % (47 mg 0.205 mmol). H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 8.12 (d, J =

7.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 2H), 6.75 (t, J =

13 7.3 Hz, 1H), 6.61 (d, J = 7.8 Hz, 2H), 4.47 (s, 2H), 4.22 (s, 1H). C NMR (125 MHz, CDCl3) δ

148.61, 147.33, 142.02, 133.20, 129.57, 129.39, 122.27, 122.07, 118.25, 112.97, 47.56.

4-Carbomethoxy-N-phenylbenzylamine. Synthesized following GP4

+ - from from 2-1a (5.2 mg, 5 μmol), Ph3C B(C6F5)4 (11.7m g,.5 μmol), 2-

5l 120.1 mg, 0.5 mmol) and phenylsilane (88 μL, 0.55 mmol) in CH2Cl2

(0.5 mL) at ambient temperature for 23.5 h. The title compound was isolated after flash column chromatography (silica gel 60 hexanes/Et2O/Et3N 44:5:1, Rf = 0.1) as a

1 clear oil. Yield 87 % (106 mg 0.439 mmol). H NMR (499 MHz CDCl3) δ 8.12 (d, J = 8.0 Hz, 2H),

7.53 (d, J = 7.9 Hz, 2H), 7.28 (t, J = 7.8 Hz, 2H), 6.84 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H),

4.48 (s, 2H), 4.29 (s, 1H), 4.01 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.97, 147.84, 145.09,

129.97, 129.33, 129.07, 127.16, 117.82, 112.93, 52.10, 47.97.

108

(rac) – N-Benzyl-α-methylbenzylamine Synthesized following GP4 from from

+ - 2-1a (5.1g, 12.5 μmol), Ph3C B(C6F5)4 (11.5 mg, 12.5 μmol), 2-5c (51.2 g, 0.25

mmol) and phenylsilane (34 μL, 0.275 mmol) in CH2Cl2 (0.5 mL) at ambient temperature for < 5 min. The title compound was isolated after flash column chromatography (silica

1 gel 60 hexanes/Et2O/Et3N 48:1:1, Rf = 0.11) as a clear oil. Yield 60 % (31 mg 0.146 mmol). H

NMR (400 MHz, CDCl3) δ 7.45 – 7.26 (m, 10H), 3.87 (q, J = 6.6 Hz, 1H), 3.72 (d, J = 13.2 Hz,

1H), 3.65 (d, J = 13.2 Hz, 1H), 1.72 (bs, J = 70.0 Hz, 1H), 1.43 (d, J = 6.6 Hz, 3H). 13C NMR (125

MHz, CDCl3) δ 145.71, 140.79, 128.60, 128.49, 128.26, 127.06, 126.97, 126.84, 126.83, 110.10,

57.63, 51.79, 24.63.

α-Phenyl-N-(phenylmethyl)-benzenemethanamine. Synthesized following

+ - GP4 from from 2-1a (2.3 mg, 5 μmol), Ph3C B(C6F5)4 (4.7 mg, 5 μmol), 2-5e

(134.2 mg, 0.5 mmol) and phenylsilane (87 μL, 0.55 mmol) in CH2Cl2 (0.5 mL)

at ambient temperature for < 5 min. The title compound was isolated after flash column chromatography (silica gel 60 hexanes/Et3N 49:1, Rf = 0.32) as an ocher oil. Yield 96 %

1 (130 mg 0.475 mmol). H NMR (499 MHz, CDCl3) δ 7.43 (dd, J = 8.2, 1.5 Hz, 4H), 7.35 – 7.26

(m, 8H), 7.25 (d, J = 5.5 Hz, 1H), 7.24 – 7.17 (m, 2H), 4.86 (s, 1H), 3.74 (d, J = 1.4 Hz, 2H), 1.86

13 (s, 1H). C NMR (101 MHz, CDCl3) δ 144.13, 140.62, 128.64, 128.52, 128.30, 127.51, 127.17,

127.06, 66.60, 52.03.

N-Benzyl-4-methyl-N-(2-propenyl)benzenesulfonamide. Synthesized

+ - following GP4 from from 2-1a (2.4 mg, 5 μmol), Ph3C B(C6F5)4 (4.6 mg, 5

μmol), 2-5m (73.7 mg, 0.5 mmol) and phenylsilane (87 μL, 0.55 mmol) in

CH2Cl2 (0.5 mL) at ambient temperature for 48 h. The hydrosilylated 2-5m was then transferred to a 25 ml round-bottom flask fitted with a stirbar. To the reduced product is added 2.25 ml 2 M KOH and 4-tosylchloride (0.150 g, 0.787 mmol) and left to stir for 24 h. The solution was then diluted

109

with 5 mL H2O and the solution extracted with 10 ml CH2Cl2 (3 x). The final solution is concentrated in vacuo and purified by silica gel column chromatography. The title compound was isolated after flash column chromatography (silica gel 60 hexanes /Et3N 49:1, Rf = 0.19) as an ocher

1 oil. Yield 96 % (130 mg 0.475 mmol). H NMR (499 MHz, CDCl3) δ 7.90 – 7.84 (m, 2H), 7.46 –

7.38 (m, 4H), 7.41 – 7.35 (m, 3H), 5.59 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.18 (dq, J = 10.1, 1.2

Hz, 1H), 5.12 (dq, J = 17.1, 1.4 Hz, 1H), 4.46 (s, 2H), 3.88 (dt, J = 6.6, 1.4 Hz, 2H), 2.55 (s, 3H).

13 C NMR (126 MHz, CDCl3) δ 143.32, 137.52, 136.02, 132.19, 129.76, 128.52, 128.47, 127.71,

127.20, 119.37, 50.22, 49.51, 21.54.

N-Benzenesulfonyl-N-benzylamine. Synthesized following GP4 from from 2-

+ - 1a (10.1 mg, 25 μmol), Ph3C B(C6F5)4 (23 mg, 25 μmol), 2-5n (123.1 mg, 0.5

mmol) and phenylsilane (87 μL, 0.55 mmol) in CH2Cl2 (0.5 mL) at ambient

temperature for 1 h. The title compound was isolated after flash column chromatography (silica gel 60 Hexanes/Et2O/Et3N 49:1, Rf = 0.32) as a white crystalline solid.

1 Yield 85 % (106 mg 0.428 mmol). H NMR (499 MHz, CDCl3) δ 7.80 – 7.73 (m, 2H), 7.50 – 7.43

(m, 2H), 7.42 – 7.35 (m, 2H), 7.18 – 7.12 (m, 3H), 7.10 – 7.04 (m, 2H), 4.83 (t, J = 5.9 Hz, 1H),

13 4.03 (d, J = 6.1 Hz, 2H). C NMR (126 MHz, CDCl3) δ 140.03, 136.31, 132.80, 129.24, 128.80,

128.03, 127.97, 127.21, 47.39.

4-Bromo-α-phenyl-N-(phenylmethyl)-benzenemethanamine. Synthesized

+ - following GP4 from from 2-1a (5.3 mg, 12.5 μmol), Ph3C B(C6F5)4 (11.6 mg,

12.5 μmol), 2-5o (87.6 mg, 0.5 mmol) and phenylsilane (43 μL, 0.275 mmol)

in CH2Cl2 (0.5 mL) at ambient temperature for 18 h. The title compound was isolated after flash column chromatography (silica gel 60 Hexanes/Et3N 49:1, Rf = 0.32) as an ocher

1 oil. Yield 97 % (86 mg 0.244 mmol). H NMR (499 MHz, CDCl3) δ 7.58 – 7.20 (m, 14H), 4.92 (s,

110

13 1H), 3.84 (s, 2H), 1.97 (s, 1H). C NMR (126 MHz, CDCl3) δ 143.58, 143.10, 140.30, 131.68,

129.20, 128.74, 128.53, 128.23, 127.39, 127.33, 127.13, 120.90, 65.93, 51.90.

4.4.8 Borenium Catalyzed Hydrosilylation of 8-Methylquinoline In a nitrogen filled glovebox, a one dram vial was charged with MIC-borane, 2-1a (3.5 mg 10

+ - μmol), and Ph3C B(C6F5)4 (9.7 mg, 10 μmol). After adding a stir bar, 0.1 mL CD2Cl2 is added by syringe. The mixture was then stirred for 1 – 2 min until the solution became homogenous and decolorized. The solution was then transfer to a J-Young NMR tube by glass pipette with washing

(3x 0.1 mL CD2Cl2). 8-Methylquinoline (27 μL, 0.2 mmol) was then added neat by μL pipette followed by phenylsilane (27 μL, 0.22 mmol). The J-Young tube was sealed, brought out of the glovebox and the reaction monitored by 1H NMR.

Table 4-1 Borenium catalyzed hydrosilylation of 8-methylquinoline.

111

1 Figure 4-3 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 20 min

1 Figure 4-4 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 1 h

112

1 Figure 4-5 H NMR of Borenium catalyzed hydrosilylation of 8-methylquinoline in CD2Cl2 at T = 18 hr

4.4.9 General Procedure for the Borohydride Catalyzed Hydrosilylation of Carbonyl Functionalities (GP5) In a nitrogen filled glovebox, a one dram equipped with a stir bar vial was charged with carbonyl compound, borohydride, solvent. While mixing the indicated silane is added by μL pipette, the vial is then sealed and reaction is left stirring. After the indicated time the vial was removed from the glovebox and 2 mL 1:1 MeOH/2 M KOH was added to the reaction mixture by glass pipette dropwise, the reaction was then left to stir for 1 h. The reaction was then acidified with 5 mL 1 M

HCl and was extracted (3 x 15 mL) with CH2Cl2. The final solution was concentrated in vacuo and purified by silica gel column chromatography.

Synthesized following GP5 from from Na-9BBN-H2 (7.7 mg, 0.050 mmol), 2-

38a (189 mg, 1.0388 mmol) and PMHS (90 μL, 1.5 mmol) in THF (1 mL) at

ambient temperature for 2 h. The title compound was isolated after flash column chromatography as an ocher solid. Yield 97 % (187 mg, 1.014 mmol). 1H NMR (400 MHz,

113

CDCl3) δ 7.38 – 7.27 (m, 8H), 7.26 – 7.18 (m, 2H), 5.78 (d, J = 2.9 Hz, 1H), 2.32 (d, J = 3.2 Hz,

13 1H). C NMR (101 MHz, CDCl3) δ 143.92, 128.60, 127.67, 126.67, 76.35.

Synthesized following GP5 from from Na-9BBN-H2 (7.7 mg, 0.050 mmol),

2-38a (40.4 mg, 0.203 mmol) and PMHS (18 μL, 0.3 mmol) in THF (1 mL)

at ambient temperature for 2 h. The title compound was isolated after flash

column chromatography as an ocher solid. Yield 93 % (38 mg, 0.189 mmol).

1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.87 (q, J = 6.4

13 Hz, 1H), 1.47 (d, J = 6.5 Hz, 3H). C NMR (101 MHz, CDCl3) δ 144.91, 131.70, 127.29, 121.31,

69.94, 25.40. SFC analysis using a CHIRALPAK IF column (length 250 mm, 4.6 mm, particle size

5 μm) was used to determine enantiomeric excess. IF column, 2mL/min, 35 MPa, 50 °C, 1% →

40% EtOH over 20 min then 40% EtOH for 1 min; tR 8.16 (major), 8.31 (minor).

1 2 BB_i-75_rac_IF_EtOH - CH10 1 2 BB_i-75_rac_IF_EtOH - CH10 300000 300000

200000 200000

Intensity[µV]

100000 100000

0 0

0.0 2.0 4.0 6.0 8.0 10.0 6.80 6.90 7.00 7.10 7.20 7.30 7.40 7.50 Retention Time [min] Retention Time [min]

BBII85_2nd_try_20150402 - CH10 BBII85_2nd_try_20150402 - CH10

200000

40000 1

2 100000 20000

Intensity[µV]

1 2

0 0

0.0 5.0 10.0 15.0 20.0 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 Retention Time [min] Retention Time [min]

Figure 4-6 Chiral SFC spectra for 2-39b racemate (above) and scalemic (below). 114

Synthesized following GP5 from from Na-9BBN-H2 (7.3 mg, 0.050 mmol), 2-

38d (156.2 mg, 1 mmol) and PMHS (90 μL, 1.5 mmol) in THF (1 mL) at

ambient temperature for 2 h. The title compound was isolated after flash column

chromatography as an ocher solid. Yield 50 % (80 mg, 0.505 mmol). 1H NMR

13 (499 MHz, CDCl3) δ 7.90 – 7.77 (m, 4H), 7.55 – 7.44 (m, 3H), 4.86 (s, 2H), 1.92 (s, 2H). C NMR

(126 MHz, CDCl3) δ 138.31, 133.38, 132.95, 128.33, 127.89, 127.72, 126.19, 125.90, 125.44,

125.17, 65.46.

Synthesized following GP5 from from Na-9BBN-H2 (7.6 mg, 0.050 mmol), 2-

38e (194.3 mg, 1 mmol) and PMHS (90 μL, 1.5 mmol) in THF (1 mL) at 60

°C for 18 h. The title compound was isolated after flash column

1 chromatography as an ocher solid. Yield 20 % (40 mg, 0.203 mmol). H NMR (400 MHz, CDCl3)

δ 3.04 (t, J = 5.7 Hz, 1H), 1.88 – 1.50 (m, 9H), 1.42 (dddt, J = 11.9, 9.1, 6.3, 3.0 Hz, 2H), 1.34 –

13 0.92 (m, 12H). C NMR (101 MHz, CDCl3) δ 80.41, 39.88, 30.00, 27.33, 26.56, 26.50, 26.18.

Synthesized following to GP5 from from Na-9BBN-H2 (0.0081 g, 55 μmol), 2-

38f (0.17185 g, 1.046 mmol) and PMHS (179 μL, 3 mmol) in THF (1 mL) at

60 °C for 18 h. The title compound was isolated after flash column chromatography as an ocher solid. Yield 20 % (0.04 g, 0.203 mmol). 1H NMR (400 MHz,

Chloroform-d) δ 7.28 (dt, J = 8.5, 6.3 Hz, 2H), 7.24 – 7.14 (m, 3H), 3.68 (t, J = 6.4 Hz, 2H), 2.78

13 – 2.62 (m, 2H), 1.97 – 1.81 (m, 2H), 1.36 (s, 1H). C NMR (101 MHz, CDCl3) δ 141.81, 128.42,

128.40, 125.87, 62.30, 34.24, 32.09.

Synthesized following GP5 from from Na-9BBN-H2 (7.4 mg, 0.050 mmol),

2-38g (158.2 mg, 1 mmol) and PMHS (90 μL, 1.5 mmol) in THF (1 mL) at

ambient temperature for 2 h. The title compound was isolated after flash

column chromatography as white crystalline solid. Yield 62 % in total (97 mg,

115

1 0.621 mmol). (cis) – 2-39g Yield 39 % (62 mg, 0.397 mmol). H NMR (400 MHz, CDCl3) δ 4.02

(s, 1H), 1.82 (d, J = 13.8 Hz, 2H), 1.59 – 1.27 (m, 17H), 0.98 (t, J = 11.6 Hz, 2H), 0.85 (s, 9H). 13C

NMR (101 MHz, CDCl3) δ 66.00, 48.16, 33.52, 27.61, 21.04. (trans) - 2-39g Yield 22 % (35 mg,

1 0.224 mmol). H NMR (400 MHz, CDCl3) δ 3.49 (tt, J = 10.9, 4.4 Hz, 1H), 2.04 – 1.91 (m, 2H),

1.81 – 1.70 (m, 3H), 1.25 – 1.14 (m, 2H), 1.10 – 0.90 (m, 4H), 0.83 (s, 9H). 13C NMR (101 MHz,

CDCl3) δ 71.28, 47.29, 36.17, 27.77, 25.72.

4.5 Chapter 4 References

1. Romanato, P.; Duttwyler, S.; Linden, A.; Baldridge, K. K.; Siegel, J. S. Intramolecular Halogen Stabilization of Silylium Ions Directs Gearing Dynamics. Journal of the American Chemical Society 2010, 132, 7828.

2. Brown, H. C.; Singaram, B.; Mathew, C. P. Addition Compounds of Alkali Metal Hydrides. 20. Reaction of Representative Mono- and Dialkylboranes with Saline Hydrides to form the Corresponding Alkylborohydrides. The Journal of Organic Chemistry 1981, 46, 2712. 3. Creary, X. TOSYLHYDRAZONE SALT PYROLYSES: PHENYLDIAZOMETHANES. Organic Syntheses 1986, 64, 207. 4. Miyano, S.; Lu, L. D. L.; Sharpless, K. B. Kinetic Resolution of Racemic beta-Hydroxy Amines by Enantioselective N-Oxide Formation. The Journal of Organic Chemistry 1985, 50, 4350. 5. Eisenberger, P.; Bestvater, B. P.; Keske, E. C.; Crudden, C. M. Hydrogenations at Room Temperature and Atmospheric Pressure with Mesoionic Carbene-Stabilized Borenium Catalysts. Angewandte Chemie International Edition 2015, 2467, 54. 6. Zoller, U. The Cheletrofic Fragmentation of Hypervalent Three-Membered Thiahetesocyclic Intermediates. Tetrahedron 1988, 44, 7413. 7. Guzen, K. P.; Guarezemini, A. S.; Orfao, A. T. G.; Cella, R.; Pereira, C. M. P.; Stefani, H. A. Eco-Friendly Synthesis of Imines by Ultrasound Irradiation. Tetrahedron Letters 2007, 48, 1845. 8. Oestreich, M.; Frohlich, R.; Vyas, D. J. Activation of the Si–B Linkage: Copper-Catalyzed Addition of Nucleophilic Silicon to Imines. Organic Letters 2011, 13, 2094.

116

9. Lam, J.; Günther, B. A. R.; Farrell, J. M.; Eisenberger, P.; Bestvater, B. P.; Newman, P. D.; Melen, R. L.; Crudden, C. M.; Stephan, D. W. Chiral Carbene–Borane Adducts: Precursors for Borenium Catalysts for Asymmetric FLP Hydrogenations. Dalton Transaction 2016, 45, 15503. 10. Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldgerg, K. I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29, 2176.

11. Eisenberger, P.; Bailey, A. M.; Crudden, C. M. Taking the F out of FLP: Simple Lewis Acid−Base Pairs for Mild Reductions with Neutral Boranes via Borenium Ion Catalysis. Journal of the American Chemical Society 2012, 134, 17384. 12. Mehrotra, K. N.; Giri, B. P. Reduction of N-Substituted Imines with Sodium in Ether. Synthesis 1977, 7, 489. 13. Fleischer, S.; Zhou, S.; Junge, K.; Beller, M. An Easy and General Iron-catalyzed Reductive Amination of Aldehydes and Ketones with Anilines. Chemistry an Asian Journal 2011, 6, 2240. 14. Shintani, R.; Hayashi, S.; Murakami, M.; Takeda, M.; Hayashi, T. Stereoselective Synthesis of Spirooxindoles by Palladium-Catalyzed Decarboxylative Cyclization of γ-Methylidene-δ- valerolactones with Isatins. Organic Letters 2009, 11, 3754. 15. Ribeiro da Silva, M. A. V.; Cabral, J. I. T. A.; Gomes, P.; Gomes, J. R. B. Combined Experimental and Computational Study of the Thermochemistry of Methylpiperidines. Journal of Organic Chemistry 2006, 71, 3677. 16. Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Kubo, H.; Ohmiya, S.; Hiroshi, T. Stereocontrolled Preparation of cis- and trans-2,6-Dialkylpiperidines via Diastereoselective Reaction of 1-Aza-4-Oxabicyclo[4.3.0]Nonane Derivatives with Grignard Reagents. Tetrahedron 1998, 54, 13955.

17. Simon, R. C.; Grischek, B.; Zepeck, F.; Steinreiber, A.; Belaj, F.; Kroutil, W. Regio- and Stereoselective Monoamination of Diketones without Protecting Groups. Angewandte Chemie International Edition 2012, 51, 6713. 18. Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.; Medina, J. R.; Matos, K.; Soderquist, J. A. 9-Borabicyclo[3.3.2]decanes and the Asymmetric Hydroboration of 1,1- Disubstituted Alkenes. Journal of the American Chemical Society 2008, 130, 9218.

117

19. Canales, E.; Prasad, K. G.; Soderquist, J. A. B-Allyl-10-Ph-9-borabicyclo[3.3.2]decanes: Strategically Designed for the Asymmetric Allylboration of Ketones. Journal of the American Chemical Society 2005, 127, 11572.

118

4.6 Appendix

Figure 4-7 1H NMR of 2-10g

119

Figure 4-8 13C NMR of 2-10g

Figure 4-9 1H NMR of 2-10h 120

Figure 4-10 13C NMR of 2-10h

Figure 4-11 1H NMR of (rac) – 2-16a. Unknown impurities at 7.9 and 8.75 ppm.

121

Figure 4-12 13C NMR of (rac) – 2-16a

Figure 4-13 11B NMR of (rac) – 2-16a

122

Figure 4-14 1H NMR of (rac) – 2-16b

Figure 4-15 13C NMR of (rac) – 2-16b

123

Figure 4-16 11B NMR of (rac) – 2-16b

Figure 4-17 1H NMR of (S) – 2-18

124

Figure 4-18 13C NMR of (S) – 2-18

Figure 4-19 11B NMR of (S) – 2-18

125

Figure 4-20 1H NMR of (rac) – 2-19a

Figure 4-21 13C NMR of (rac) – 2-19a

126

Figure 4-22 11B NMR of (rac) – 2-19a

Figure 4-23 1H NMR of (rac) – 2-21a

127

Figure 4-24 13C NMR of (rac) – 2-21a

Figure 4-25 11B NMR of (rac) – 2-21a

128

Figure 4-26 1H NMR of 2-6h

Figure 4-27 13C NMR of 2-6h

129

Figure 4-28 1H NMR of 2-6i

Figure 4-29 13C NMR of 2-6i

130

Figure 4-30 1H NMR of 2-6j

Figure 4-31 13C NMR of 2-6j

131

Figure 4-32 19F NMR of 2-6j

Figure 4-33 1H NMR of 2-6k

132

Figure 4-34 13C NMR of 2-6k

Figure 4-35 1H NMR of 2-6l

133

Figure 4-36 13C NMR of 2-6l

Figure 4-37 1H NMR of 2-6e

134

Figure 4-38 13C NMR of 2-6e

Figure 4-39 1H NMR of 2-6e

135

Figure 4-40 13C NMR of 2-6e

Figure 4-41 1H NMR of 2-6m

136

Figure 4-42 13C NMR of 2-6m

Figure 4-43 1H NMR of 2-6n

137

Figure 4-44 13C NMR of 2-6n

Figure 4-45 1H NMR of 2-6o

138

Figure 4-46 13C NMR of 2-6o

Figure 4-47 1H NMR of 2-39a

139

Figure 4-48 13C NMR of 2-39a

Figure 4-49 1H NMR of 2-39b

140

Figure 4-50 13C NMR of 2-39b

Figure 4-51 1H NMR of 2-39d

141

Figure 4-52 13C NMR of 2-39d

Figure 4-53 1H NMR of 2-39e

142

Figure 4-54 13C NMR of 2-39e

Figure 4-55 1H NMR of 2-39f

143

Figure 4-56 13C NMR of 2-39f

Figure 4-57 1H NMR of (cis) – 2-39g

144

Figure 4-58 13C NMR of (cis) – 2-39g

Figure 4-59 1H NMR of (trans) – 2-39g

145

Figure 4-60 13C NMR of (trans) – 2-39g

146